Compounds with growth hormone releasing properties

ABSTRACT

Novel peptide derivatives, compositions containing them, and their use for treating medical disorders resulting from a deficiency in growth hormone are disclosed. The peptides have the formula (I): ##STR1## wherein a, b, A, R 1 , L 1 , D, R 3 , R 4 , R 2 , L 2 , E and G are as defined in the specification. These peptides exhibit improved resistance to proteolytic degradation, and hence, improved bioavailability.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. 119 of Danishapplication Ser. No. 0803/96 filed Jul. 22, 1996, the contents of whichare fully incorporated herein by reference.

FIELD OF INVENTION

The present invention relates to novel compounds, pharmaceuticalcompositions containing them, a method of stimulating the release ofgrowth hormone from the pituitary, a method for increasing the rate andextent of growth of animals to increase their milk and wool production,or for the treatment of ailments, and to use of the compounds for thepreparation of medicaments.

BACKGROUND OF THE INVENTION

Growth hormone is a hormone which stimulates growth of all tissuescapable of growing. In addition, growth hormone is known to have anumber of effects on metabolic processes, e.g., stimulation of proteinsynthesis and free fatty acid mobilization and to cause a switch inenergy metabolism from carbohydrate to fatty acid metabolism. Deficiencyin growth hormone can result in a number of severe medical disorders,e.g., dwarfism.

Growth hormone is released from the pituitary. The release is undertight control of a number of hormones and neurotransmitters eitherdirectly or indirectly. Growth hormone release can be stimulated bygrowth hormone releasing hormone (GHRH) and inhibited by somatostatin.In both cases the hormones are released from the hypothalamus but theiraction is mediated primarily via specific receptors located in thepituitary. Other compounds which stimulate the release of growth hormonefrom the pituitary have also been described. For example arginine,L-3,4-dihydroxyphenylalanine (L-Dopa), glucagon, vasopressin, PACAP(pituitary adenylyl cyclase activating peptide), muscarinic receptoragonists and a synthethic hexapeptide, GHRP (growth hormone releasingpeptide) release endogenous growth hormone either by a direct effect onthe pituitary or by affecting the release of GHRH and/or somatostatinfrom the hypothalamus.

In disorders or conditions where increased levels of growth hormone isdesired, the protein nature of growth hormone makes anything butparenteral administration non-viable. Furthermore, other directly actingnatural secretagogues, e.g., GHRH and PACAP, are longer polypeptides forwhich reason oral administration of them is not viable.

The use of certain compounds for increasing the levels of growth hormonein mammals has previously been proposed, e.g. in EP 18 072, EP 83 864,WO 89/07110, WO 89/01711, WO 89/10933, WO 88/9780, WO 83/02272, WO91/18016, WO 92/01711, WO 93/04081, WO 95/17422, WO 95/17423, WO95/14666, WO 96/15148 and WO 96/10040.

The composition of growth hormone releasing compounds is important fortheir growth hormone releasing potency as well as their bioavailability.It is therefore an object of the present invention to provide novelcompounds with growth hormone releasing properties.

SUMMARY OF INVENTION

Accordingly, the present invention relates to a compound of the generalformula I ##STR2## wherein A is A¹ or A² ;

G is G¹ or G² ;

D is hydrogen, --O--(CH₂)_(k) --R^(5a), ##STR3## wherein R⁵, R⁶, R⁷, R⁸,and R⁹ independently are hydrogen, halogen, aryl, C₁₋₆ -alkyl or C₁₋₆-alkoxy;

R^(5a) is hydrogen, aryl optionally substituted with halogen or C₁₋₆-alkyl, or C₁₋₆ -alkyl optionally substituted with halogen or C₁₋₆-alkyl, k is 0, 1, 2, or 3;

E is hydrogen, --O--(CH₂)_(l) --R^(10a), ##STR4## wherein R¹⁰, R¹¹, R¹²,R¹³ and R¹⁴ independently are hydrogen, halogen, aryl, C₁₋₆ -alky, C₁₋₆-alkoxy, --CONR¹⁵ R¹⁶, --(CH₂)_(v) --NR¹⁵ SO₂ R¹⁷, --(CH₂)_(v) --NR¹⁵COR¹⁶, --(CH₂)_(v) --OR ¹⁷, --(CH₂)_(v) --OR¹⁷, --(CH₂)_(v--OCOR) ¹⁶,--CH(R¹⁵)R¹⁶, --(CH₂)_(v) --NR¹⁵ --CS--NR¹⁶ R¹⁸, --(CH₂)_(v) --NR¹⁵--CO--NR¹⁶ R¹⁸, ##STR5## wherein X¹ is --N(R¹⁹)--, --O-- or --S--,

X² is --C(R²⁰)═ or --N═,

X³ is --C(R²¹)═ or --N═,

X⁴ is --C(R²²)═ or --N═;

R² and R¹⁰ may be taken together to form --CH₂ -- or --CH₂ --CH₂ --,

R¹⁹ is hydrogen or C₁₋₆ -alkyl optionally substituted with aryl,

R²⁰, R²¹ and R²² independently are hydrogen, --COOR²³, --CONR²⁴ R²⁵,--(CH₂)_(w) NR²⁴ R²⁵, --(CH₂)_(w) OR²³, --(CH₂)_(w) R²³ or halogen;

R¹⁵, R¹⁶, R²³, R²⁴ and R²⁵ independently are hydrogen or C₁₋₆ -alkyloptionally substituted with halogen, --N(R²⁶)R²⁷, hydroxyl, C₁₋₆-alkoxy, C₁₋₆ -alkoxycarbonyl, C₁₋₆ -alkyl-carbonyloxy or aryl,

or R¹⁶ is ##STR6## wherein Q¹ is --CH<or --N<,

T¹ and J¹ are independently --CH₂ --, --CO--, --O--, --S--, --NR²⁸ -- ora valence bond,

where R²⁸ is hydrogen or linear or branched C₁₋₆ -alkyl;

t and u are independently 0, 1, 2, 3 or 4;

R¹⁷ is C₁₋₆ alkyl or phenyl optionally substituted with hydroxyl oraryl;

R¹⁸ is C₁₋₆ alkyl;

R²⁶ and R²⁷ are independently hydrogen or C₁₋₆ -alkyl;

v and w are independently 0, 1, 2 or 3;

R^(10a) is hydrogen, aryl optionally substituted with halogen or C₁₋₆-alkyl, or C₁₋₆ -alkyl optionally substituted with halogen or C₁₋₆-alkyl,

l is 0, 1, 2, or 3;

A¹ is ##STR7## wherein R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵ and R³⁶ areindependently hydrogen or C₁₋₆ -alkyl optionally substituted withhalogen, amino, hydroxyl or aryl;

R³³ and R³⁴, R³³ and R³⁵, or R³⁴ and R³⁵ may optionally form --(CH₂)_(i)--Z--(CH₂)_(j), wherein i and j independently are 1 or 2 and Z is --O--,--S-- or a valence bond;

n, m and q are independently 0, 1, 2, or 3;

o and p are independently 0 or 1;

M is --CR³⁷ ═CR³⁸ --, --O--, --S--, or a valence bond;

R³⁷ and R³⁸ are independently hydrogen, or C₁₋₆ -alkyl optionallysubstituted with aryl;

A² is ##STR8## wherein R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵ and R³⁶ areindependently hydrogen or C₁₋₆ -alkyl optionally substituted withhalogen, amino, hydroxyl or aryl;

R³³ and R³⁴, R³³ and R³⁵ or R³⁴ and R³⁵ may optionally form --(CH₂)_(i)--Z--(CH₂)_(j) --, wherein i and j independently are 1 or 2 and Z is--O--, --S-- or a valence bond;

n, m and q are independently 0, 1, 2, or 3;

o and p are independently 0 or 1;

M is --CR³⁷ ═CR³⁸ --, --O--, or --S--;

R³⁷ and R³⁸ are independently hydrogen, or C₁₋₆ -alkyl optionallysubstituted with aryl; G¹ is hydrogen, halogen, aryl, C₁₋₆ -alkyl, C₁₋₆-alkoxy, --CONR³⁹ R⁴⁰, --(CH₂)_(e) --NR³⁹ SO₂ R⁴¹, --(CH₂)_(e) --NR ³⁹COR⁴⁰, --(CH₂)_(e) --OR⁴¹, --(CH₂)_(e) --OCOR⁴⁰, --CH(R³⁹)R⁴⁰, --CON³⁹--NR⁴⁰ R⁴², --(CH₂)_(e) --NR³⁹ --CS--NR⁴⁰ R⁴², --(CH₂)_(e) --NR³⁹--CO--NR⁴⁰ R⁴², ##STR9## wherein X⁵ is --N(R⁴³)--, --O-- or --S--,

X⁶ is --C(R⁴⁴)═ or --N═,

X⁷ is --C(R⁴⁵)═ or --N═,

X⁸ is --C(R⁴⁶)═ or --N═,

R⁴³ is hydrogen or C₁₋₆ -alkyl optionally substituted with aryl,

R⁴³, R⁴⁵ and R⁴⁶ independently are hydrogen, --COOR⁴⁷, --CONR⁴⁸ R⁴⁹,--(CH₂)_(f) NR⁴⁸ R⁴⁹, --(CH₂)_(f) OR⁴⁷, --(CH₂)_(f) R⁴⁷ or halogen;

R³⁹, R⁴⁰, R⁴⁷, R⁴⁸ and R⁴⁹ independently are hydrogen or C₁₋₆ -alkyloptionally substituted with halogen,

--N(R⁵⁰)R⁵¹, hydroxyl, C₁₋₆ alkoxy, C₁₋₆ -alkoxycarbonyl, C₁₋₆-alkylcarbonyloxy or aryl,

or R⁴⁰ is ##STR10## wherein Q² is --CH<or --N<,

J² and T² are independently --CH₂ --, --CO--, --O--, --S--, --NR⁵² -- ora valence bond,

where R⁵² is hydrogen or C₁₋₆ -alkyl;

x and y are independently 0, 1, 2, 3 or 4;

R⁴¹ is C₁₋₆ alkyl substituted with aryl;

R⁴² is C₁₋₆ alkyl;

R⁵⁰ and R⁵¹ are independently hydrogen or C₁₋₆ -alkyl;

e and f are independently 0, 1, 2 or 3;

G² is hydrogen or C₁₋₆ -alkyl;

R¹ is hydrogen or C₁₋₆ -alkyl;

R² is hydrogen, --C(═O)--R⁵⁴ or C₁₋₆ -alkyl;

R¹ and R² may be taken together to form a bridge of type ##STR11##wherein R⁵⁵ and R⁵⁶ independently of each other are hydrogen, C₁₋₆-alkyl, optionally substituted with hydroxyl, C₁₋₆ -alkoxyl or aryl;

R⁵⁵ and R⁵⁶ may be taken together to form ═0 or ═S;

c and d are independently 0, 1, or 2;

c+d is 0, 1, or 2;

R⁵⁴ is hydrogen or C₁₋₆ -alkyl,

R³ and R⁴ are hydrogen, C₁₋₆ -alkyl, optionally substituted withhydroxyl, C₁₋₆ -alkoxyl, halogen, or aryl;

R³ and R⁴ may be taken together to form ═S, ═O;

L¹ is CR⁵⁷ or N;

L² is CR⁵⁸ or N;

R⁵⁷ and R⁵⁸ independently are hydrogen, C₁₋₆ -alkyl, optionallysubstituted with hydroxyl, halogen, C₁₋₆ -alkoxy, or aryl;

a and b independently are 0, 1, 2, or 3;

with the proviso that

when G is G² and L¹ is CR⁵⁵ and L² is CR⁵⁶, then A is A² ;

when G is G¹ and L¹ is CR⁵⁵ and L² is CR⁵⁶, then A is A¹ and R² is--C(═O)--R⁵⁴ or R¹ and R² are taken together to form a bridge of thetype ##STR12## when either of L¹ or L² is N, then G is G¹ and A is A¹ ;

or a pharmaceutically acceptable salt thereof.

In one embodiment of the compound of formula I A is

    R.sup.33 --NH--(CR.sup.34 R.sup.35).sub.p.(CH.sub.2).sub.m --M--(CHR.sup.36).sub.o --(CH.sub.2).sub.n --

wherein R³³ is hydrogen or C₁₋₆, alkyl optionally substituted withhydroxyl, preferably hydrogen, methyl or hydroxypropyl, e.g.(2R)-2-hydroxypropyl,

R³⁴ and R³⁵ are independently of each other C₁₋₆ alkyl, preferablymethyl,

R³⁶ is hydrogen,

M is --CR³⁷ ═CR³⁸ -- or --O--, wherein R³⁷ and R³⁸ are hydrogen or C₁₋₆alkyl, preferably --CH═CH-- or O,

p is 1, m is 1, o is 0 or 1 and n is 0 or 1.

In another embodiment of the compound of formula I A is ##STR13##wherein M is --O-- or --S--, preferably --O--, o is 0 or 1, preferably1,

q is 0, 1 or 2, preferably 1, and

m+n is 3 or 4, preferably 3.

In a further embodiment of the compound of formula I A is ##STR14##wherein R³³ is hydrogen or C₁₋₆ alkyl, preferably, hydrogen, R³⁴ and R³⁵independently of each other are hydrogen or C₁₋₆ alkyl, preferablyhydrogen or methyl, m is 0 or 1, n is 0 or 1, preferably 0 and p is 0or 1. In particular the phenylen moiety is meta-substituted, however itmight be ortho- or para-substituted as well and the invention is by nomeans limited hereto.

In the above compound of formula I A is preferably(1E)-4-amino-4-methylbut-1-enyl, (1E)-4-amino-4-methylpent-1-enyl(2-amino-2-methylpropyxy)methyl, ((2S)-pyrrolidin-2-yl)methoxymethyl,4-piperidinyl, (1E)-4-((2R)-2-hydroxypropylamino)-4-methylbut-1-enyl,(1E)-4-((2R)-2-hydroxypropylamino)-4-methylpent-1-enyl,(1E)-4-methyl-4-methylaminopent-1-enyl, 3-(1-aminoethyl)phenyl or3-(aminomethyl)phenyl. In one embodiment hereof A is (1E)-4-amino4-methylbut-1-enyl, (2-amino-2-methylpropoxy)methyl,((2S)-pyrrolidin-2-yl)methoxymethyl, 4-piperidinyl or(1E)-4-((2R)-2-hydroxypropylamino)-4-methylbut-1-enyl.

In one embodiment of the compound of formula I D is ##STR15## whereinR⁵, R⁶, R⁷, R⁸ and R⁹ independently of each other are hydrogen or aryl,preferably hydrogen or phenyl. More preferred R⁵, R⁶, R⁸ and R⁹ arehydrogen and R⁷ is phenyl.

In a further embodiment of the compound of formula I D is ##STR16##wherein R⁵ and R⁶ independently of each other are hydrogen or C₁₋₆alkyl, preferably hydrogen.

In the above compound of formula I D is preferably (2-naphthyl),benzyloxy, or biphenyl-4-yl. More preferred (2-naphthyl) orbiphenyl-4-yl.

In one embodiment of the compound of formula I E is ##STR17## whereinR¹⁰ and R¹¹ independently of each other are hydrogen or C₁₋₆ alkyl,preferably hydrogen.

In a further embodiment of the compound of formula I E is ##STR18##wherein R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ independently of each other arehydrogen, --(CH₂)_(v) --NR¹⁵ SO₂ R¹⁷, --(CH₂)_(v) --NR¹⁵ COR¹⁶ or--(CH₂)_(v) --OR¹⁷, wherein v is 0 or 1, preferably 0, R¹⁵ is hydrogenor C₁₋₆ alkyl, preferably hydrogen, R¹⁶ is hydrogen or C₁₋₆ alkyloptionally substituted with --N(R²⁶)R²⁷, wherein R²⁶ and R²⁷independently of each other are hydrogen or C₁₋₆ alkyl, preferably R¹⁶is hydrogen or C₁₋₆ alkyl substituted with amino, R¹⁷ is C₁₋₆ alkyl orphenyl optionally substituted with hydroxyl or phenyl, preferablymethyl, C₁₋₆ alkyl substituted with hydroxyl, e.g. --CH₂ CH₂ OH or --CH₂CH₂ CH₂ OH, or phenyl. In particular the phenylen moiety isortho-substituted, however it may also be meta- or para-substituted andthe invention is by no means limited hereto. In one embodiment, when R¹⁰or R¹⁴ is --(CH₂)_(v) --NR¹⁵ SO₂ R¹⁷, v is 0, R¹⁵ is hydrogen, and R¹⁷is C₁₋₆ alkyl or phenyl, preferably methyl or phenyl. In a secondembodiment, when R¹⁰ or R¹⁴ is --(CH₂)_(v) --NR¹⁵ COR¹⁶, v is 0, R¹⁵ ishydrogen and R¹⁶ is hydrogen or C₁₋₆ alkyl substituted with --NH₂,preferably aminomethyl. In a third embodiment, when R¹⁰ or R¹⁴ is--(CH₂)_(v) --OR¹⁷, v is 0, and R¹⁷ is C₁₋₆ alkyl substituted withhydroxyl, preferably --CH₂ CH₂ OH or --CH₂ CH₂ CH₂ OH.

In the above compound of formula I E is preferably phenyl, 2-thienyl,2-(2-hydroxyethoxy)phenyl, 2-(3-hydroxypropoxy)phenyl, biphenyl-4-yl,2-(aminoacetylamino)phenyl, 2-(phenylsulfonylamino)phenyl or2-(methylsulfonylamino)phenyl. In one embodiment hereof E is phenyl,2-thienyl or 2-(methylsulfonylamino)phenyl.

In one embodiment of the compound of formula I G is hydrogen or --CONR³⁹R⁴⁰, wherein R³⁹ and R⁴⁰ independently of each other are hydrogen orC₁₋₆ alkyl, preferably hydrogen, methyl or ethyl. In the above compoundof formula I G is preferably hydrogen, methyl, methylcarbamoyl, orethylcarbamoyl.

In one embodiment of the compound of formula I R¹ is hydrogen or C₁₋₆alkyl, preferably hydrogen or C₁₋₄ alkyl.

In the above compound of formula I R¹ is preferably hydrogen or methyl.

In one embodiment of the compound of formula I R² is hydrogen,--C(═O)--R⁵⁴ or C₁₋₆ alkyl, wherein R⁵⁴ is C₁₋₆ alkyl, preferablyhydrogen, C₁₋₆ alkyl or --C(═O)--CH₃.

In the above compound of formula I R² is preferably methyl, hydrogen, oracetyl.

In the above compound of formula I R¹ and R² may be taken together toform a bridge of type ##STR19## wherein R⁵⁵ and R⁵⁶ are hydrogen, or R⁵⁵and R⁵⁶ may be taken together to form ═O or ═S, preferably ═O;

c and d are independently 0, 1, or 2, preferably 0 or 1;

c+d is 0, 1, or 2, preferably 1.

In the above compound of formula I R¹ and R² may be taken together toform a bridge of type --CH₂ --C(═O)-- or --CH₂ --CH₂ --.

In the above compound of formula I R² and R¹⁰ may be taken together toform --(CH₂)_(r) --, wherein r is 1, 2 or 3, preferably 1 or 2, morepreferred 1. In a preferred embodiment E is phenyl, wherein R¹¹ to R¹⁴is hydrogen and R¹⁰ is taken together with R² to form --(CH₂)_(r) --.

In one embodiment of the compound of formula I R³ is hydrogen or C₁₋₆alkyl, preferably hydrogen.

In one embodiment of the compound of formula I R⁴ is hydrogen or C₁₋₆alkyl, preferably hydrogen.

In the above compound of formula I R³ and R⁴ may be taken together toform ═O.

In the above compound of formula I a is preferably 1.

In the above compound of formula I b is preferably 0 or 1.

In the above compound of formula I L¹ is preferably --CH--.

In the above compound of formula I L² is preferably --CH-- or >N--.

One embodiment of the compound of formula I relates to a compound of thegeneral formula II ##STR20## wherein L¹ is CR⁵⁷ or N;

L² is CR⁵⁸ or N;

R⁵⁷ and R⁵⁸ independently are hydrogen, C₁₋₆ -alkyl, optionallysubstituted with hydroxyl, halogen, C₁₋₆ -alkoxy, or aryl;

with the proviso that either L¹ or L² is N; and A¹, R¹, R², R³, R⁴, G¹,D, E, a, and b are defined above;

or a pharmaceutically acceptable salt thereof.

In one embodiment of the compound of formula II A¹ is

    R.sup.33 --NH--(CR.sup.34 R.sup.35).sub.p.(CH.sub.2).sub.m --M--(CHR.sup.36).sub.o --(CH.sub.2).sub.n --

wherein R³³ is hydrogen or C₁₋₆ alkyl optionally substituted withhydroxyl, preferably hydrogen, methyl or hydroxypropyl, e.g.(2R)-2-hydroxypropyl,

R³⁴ and R³⁵ are independently of each other C₁₋₆ alkyl, preferablymethyl,

R³⁶ is hydrogen,

M is --CR³⁷ ═CR³⁸ -- or --O--, wherein R³⁷ and R³⁸ are hydrogen or C₁₋₆alkyl, preferably --CH═CH-- or O

p is 1, m is 1, o is 0 or 1 and n is 0 or 1.

In another embodiment of the compound of formula II A¹ is ##STR21##wherein M is --O-- or --S--, preferably --O--, o is 0 or 1, preferably1,

q is 0, 1 or 2, preferably 1, and

m+n is 3 or 4, preferably 3.

In a further embodiment of the compound of formula II A¹ is ##STR22##wherein R³³ is hydrogen or C₁₋₆ alkyl, preferably, hydrogen, R³⁴ and R³⁵independently of each other are hydrogen or C₁₋₆ alkyl, preferablyhydrogen or methyl,

m is 0 or 1, n is 0 or 1, preferably 0 and p is 0 or 1. In particularthe phenylen moiety is meta-substituted, however it might be ortho- orpara-substituted as well and the invention is by no means limitedhereto.

In the above compound of formula II A¹ is preferably(1E)-4-amino-4-methylbut-1-enyl, (1E)-4-amino-4-methylpent-1-enyl(2-amino-2-methylpropoxy)methyl, ((2S)-pyrrolidin-2-yl)methoxymethyl,4-piperidinyl, (1E)-4-((2R)-2-hydroxypropylamino)-4-methylbut-1-enyl,(1E)-4-((2R)-2-hydroxypropylamino)4-methylpent-1-enyl,(1E)-4-methyl-4-methylaminopent-1-enyl, 3-(1-aminoethyl)phenyl or3-(aminomethyl)phenyl. In one embodiment hereof A¹ is(1E)-4-amino-4-methylbut-1-enyl, (2-amino-2-methylpropyxy)methyl,((2S)-pyrrolidin-2-yl)methoxymethyl, 4-piperidinyl, or(1E)-4-((2R)-2-hydroxypropylamino)-4-methylbut-1-enyl. In anotherembodiment hereof A¹ is (1E)-4-amino-4-methylpent-1-enyl,(2-amino-2-methylpropyxy)methyl or ((2S)-pyrrolidin-2-yl)methoxymethyl.

In one embodiment of the compound of formula II D is ##STR23## whereinR⁵, R⁶, R⁷, R⁸ and R⁹ independently of each other are hydrogen or aryl,prefarably hydrogen or phenyl. More preferred R⁵, R⁶, R⁸ and R⁹ arehydrogen and R⁷ is phenyl.

In a further embodiment of the compound of formula II D is ##STR24##wherein R⁵ and R⁶ independently of each other are hydrogen or C₁₋₆alkyl, preferably R⁵ and R⁶ are both hydrogen.

In the above compound of formula II D is preferably (2-naphthyl),benzyloxy, or biphenyl-4-yl. More preferred (2-naphthyl) orbiphenyl-4-yl. In one embodiment 2-naphthyl.

In one embodiment of the compound of formula II E is ##STR25## whereinR¹⁰ and R¹¹ independently of each other are hydrogen or C₁₋₆ alkyl,preferably hydrogen.

In another embodiment of the compound of formula II E is ##STR26##wherein R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ independently of each other arehydrogen, --(CH₂)_(v) --NR¹⁵ SO₂ R¹⁷, --(CH₂)_(v) --NR¹⁵ COR¹⁶ or--(CH₂)_(v) --OR¹⁷, wherein v is 0 or 1, perferably 0, R¹⁵ is hydrogenor C₁₋₆ alkyl, preferably hydrogen, R¹⁶ is hydrogen or C₁₋₆ alkyloptionally substituted with --N(R²⁶)R²⁷, wherein R²⁶ and R²⁷independently of each other are hydrogen or C₁₋₆ alkyl, preferably R¹⁶is hydrogen or C₁₋₆ alkyl substituted with amino, R¹⁷ is C₁₋₆ alkyl orphenyl optionally substituted with hydroxyl or phenyl, preferablymethyl, C₁₋₆ alkyl substituted with hydroxyl, e.g. --CH₂ CH₂ OH or --CH₂CH₂ CH₂ OH, or phenyl. In particular the phenylen moiety isortho--substituted, however it may also be meta- or para--substitutedand the invention is by no means limited hereto. In one embodiment, whenR¹⁰ or R¹⁴ is --(CH₂)_(v) --NR¹⁵ SO₂ R¹⁷, v is 0, R¹⁵ is hydrogen, andR¹⁷ is C₁₋₆ alkyl or phenyl, preferably methyl or phenyl. In a secondembodiment, when R¹⁰ or R¹⁴ is --(CH₂)_(v) --NR¹⁵ COR¹⁶, v is 0, R¹⁵ ishydrogen and R¹⁶ is hydrogen or C₁₋₆ alkyl substituted with --NH₂,preferably aminomethyl. In a third embodiment, when R¹⁰ or R¹⁴ is--(CH₂)_(v) --OR¹⁷, v is 0, and R¹⁷ is C₁₋₆, alkyl substituted withhydroxyl, preferably --CH₂ CH₂ OH or --CH₂ CH₂ CH₂ OH.

In the above compound of formula II E is preferably phenyl, 2-thienyl,2-(2-hydroxyethoxy)phenyl, 2-(3-hydroxypropoxy)phenyl, biphenyl-4-yl,2-(aminoacetylamino)phenyl, 2-(phenylsulfonylamino)phenyl or2-(methylsulfonylamino)phenyl. In one embodiment hereof E is phenyl,2-thienyl or 2-(methylsulfonylamino)phenyl, preferably phenyl, or2-thienyl, more preferred phenyl.

In one embodiment of the compound of formula II G¹ is hydrogen or--CONR³⁹ R⁴⁰, wherein R³⁹ and R⁴⁰ independently of each other arehydrogen or C₁₋₆ alkyl, preferably one of R³⁹ or R⁴ is hydrogen and theother is methyl or ethyl.

In the above compound of formula II G¹ is preferably hydrogen,methylcarbamoyl, or ethylcarbamoyl.

In one embodiment of the compound of formula II R¹ is C₁₋₆ alkyl,preferably hydrogen or C₁₋₄ alkyl.

In the above compound of formula II R¹ is preferably methyl.

In one embodiment of the compound of formula II R² is hydrogen,--C(═O)--R⁵⁴ or C₁₋₆ alkyl, wherein R⁵⁴ is C₁₋₆ alkyl, preferablyhydrogen, C₁₋₆ alkyl or --C(═O)--CH₃.

In the above compound of formula II R² is preferably methyl, hydrogen,or acetyl, more preferred methyl or hydrogen, most preferred hydrogen.

In the above compound of formula II R¹ and R² may be taken together toform a bridge of type ##STR27## wherein R⁵⁵ and R⁵⁶ are hydrogen, or R⁵⁵and R⁵⁶ may be taken together to form ═O or ═S, preferably ═O;

c and d are independently 0, 1, or 2, preferably 0 or 1;

c+d is 0, 1, or 2, preferably 1.

In one embodiment of the above compound of formula II R¹ and R² may betaken together to form a bridge of type --CH₂ --C(═O)--. In anotherembodiment of the above compound of formula II R¹ and R² may be takentogether to form a bridge of the type --CH₂ --CH₂ --.

In one embodiment of the compound of formula II R³ is hydrogen or C₁₋₆alkyl, preferably hydrogen.

In one embodiment of the compound of formula II R⁴ is hydrogen or C₁₋₆alkyl, preferably hydrogen.

In the above compound of formula II R³ and R⁴ may be taken together toform ═O.

In the above compound of formula II a is preferably 1.

In the above compound of formula II b is preferably 1.

In the above compound of formula II L¹ is preferably --CH--.

In the above compound of formula II L² is preferably --CH-- or >N--.

A further embodiment of the compound of formula I relates to a compoundof the general formula III ##STR28## wherein A¹, D, E, G¹, R³, R⁴, R⁵⁵,R⁵⁶, R⁵⁷, R⁵⁸, a, b, c, and d are defined above; or a pharmaceuticallyacceptable salt thereof.

In one embodiment of the compound of formula III A¹ is

    R.sup.33 --NH--(CR.sup.34 R.sup.35).sub.p.(CH.sub.2).sub.m --M--(CHR.sup.36).sub.o --(CH.sub.2).sub.n --

wherein R³³ is hydrogen or C₁₋₆ alkyl optionally substituted withhydroxyl, preferably hydrogen, methyl or hydroxypropyl, more preferredhydrogen,

R³⁴ and R³⁵ are independently of each other C₁₋₆ alkyl, preferablymethyl,

R³⁶ is hydrogen,

M is --CR³⁷ ═CR³⁸ -- or --O--, wherein R³⁷ and R³⁸ are hydrogen or C₁₋₆alkyl, preferably --CH═CH--,

p is 1, m is 1, o is 0 or 1, preferably 0 and n is 0 or 1, preferably 0.

In another embodiment of the compound of formula III A¹ is ##STR29##wherein M is --O-- or --S--, preferably --O--, o is 0 or 1, preferably1,

q is 0, 1 or 2, preferably 1, and

m+n is 3 or 4, preferably 3.

In a further embodiment of the compound of formula III A¹ is ##STR30##wherein R³³ is hydrogen or C₁₋₆ alkyl, preferably, hydrogen, R³⁴ and R³⁵independently of each other are hydrogen or C₁₋₆ alkyl, preferablyhydrogen or methyl,

m is 0 or 1, n is 0 or 1, preferably 0 and p is 0 or 1. In particularthe phenylen moiety is meta-substituted, however it might be ortho- orpara-substituted as well and the invention is by no means limitedhereto.

In the above compound of formula III A¹ is preferably(1E)-4-amino-4-methylbut-1-enyl, (1E)-4-amino-4-methylpent-1-enyl(2-amino-2-methylpropyxy)methyl, ((2S)-pyrrolidin-2-yl)methoxymethyl,4-piperidinyl, (1E)-4-((2R)-2-hydroxypropylamino)-4-methylbut-1-enyl,(1E)-4-((2R)-2-hydroxypropylamino)-4-methylpent-1-enyl,(1E)-4-methyl-4-methylaminopent-1-enyl 3-(1-aminoethyl)phenyl or3-(aminomethyl)phenyl. In one embodiment hereof A¹ is(1E)-4-amino4-methylbut-1-enyl, (2-amino-2-methylpropyxy)methyl or((2S)-pyrrolidin-2-yl)methoxymethyl. In another embodiment hereof A¹ is(1E)-4-amino-4-methylpent-1-enyl.

In one embodiment of the compound of formula III D is ##STR31## whereinR⁵, R⁶, R⁷, R⁸ and R⁹ independently of each other are hydrogen or aryl,prefarably hydrogen or phenyl. More preferred R⁵, R⁶, R⁸ and R⁹ arehydrogen and R⁷ is phenyl.

In a further embodiment of the compound of formula III D is ##STR32##wherein R⁵ and R⁶ independently of each other are hydrogen or C₁₋₆alkyl, preferably R⁵ and R⁶ are both hydrogen.

In the above compound of formula III D is preferably (2-naphthyl),benzyloxy, or biphenyl-4-yl. More preferred (2-naphthyl).

In one embodiment of the compound of formula III E is ##STR33## whereinR¹⁰ and R¹¹ independently of each other are hydrogen or C₁₋₆ alkyl,preferably hydrogen.

In a further embodiment of the compound of formula III E is ##STR34##wherein R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ independently of each other arehydrogen, --(CH₂)_(v) --NR¹⁵ SO₂ R¹⁷, --(CH₂)_(v) --NR¹⁵ COR¹⁶ or--(CH₂)_(v) --OR¹⁷, wherein v is 0 or 1, preferably 0, R¹⁵ is hydrogenor C₁₋₆ alkyl, preferably hydrogen, R¹⁶ is hydrogen or C₁₋₆ alkyloptionally substituted with --N(R²⁶)R²⁷, wherein R²⁶ and R²⁷independently of each other are hydrogen or C₁₋₆ alkyl, preferably R¹⁶is hydrogen or C₁₋₆ alkyl substituted with amino, R¹⁷ is C₁₋₆ alkyl orphenyl optionally substituted with hydroxyl or phenyl, preferablymethyl, C₁₋₆ alkyl substituted with hydroxyl, e.g. --CH₂ CH₂ OH or --CH₂CH₂ CH₂ OH, or phenyl. In particular the phenylen moiety isortho-substituted, however it may also be meta- or para-substituted andthe invention is by no means limited hereto. In one embodiment, when R¹⁰or R¹⁴ is --(CH₂)_(v) --NR¹⁵ SO₂ R¹⁷, v is 0, R¹⁵ is hydrogen, and R¹⁷is C₁₋₆ alkyl or phenyl, preferably methyl or phenyl. In a secondembodiment, when R¹⁰ or R¹⁴ is --(CH₂)_(v) --NR¹⁵ COR¹⁶, v is 0, R¹⁵ ishydrogen and R¹⁶ is hydrogen or C₁₋₆ alkyl substituted with --NH₂,preferably aminomethyl. In a third embodiment, when R¹⁰ or R¹⁴ is--(CH₂)_(v) --OR¹⁷, v is 0, and R¹⁷ is C₁₋₆ alkyl substituted withhydroxyl, preferably --CH₂ CH₂ OH or --CH₂ CH₂ CH₂ OH.

In the above compound of formula I E is preferably phenyl, 2-thienyl,2-(2-hydroxyethoxy)phenyl, 2-(3-hydroxypropoxy)phenyl, biphenyl-4-yl,2-(aminoacetylamino)phenyl, 2-(phenylsulfonylamino)phenyl or2-(methylsulfonylamino)phenyl. In one embodiment hereof E is phenyl,2-thienyl or 2-(methylsulfonylamino)phenyl, preferably phenyl.

In one embodiment of the compound of formula III G¹ is hydrogen or--CONR³⁹ R⁴⁰, wherein R³⁹ and R⁴⁰ independently of each other arehydrogen or C₁₋₆ alkyl, preferably hydrogen or methyl.

In the above compound of formula III G¹ is preferably hydrogen ormethylcarbamoyl.

In one embodiment of the compound of formula III R³ is hydrogen or C₁₋₆alkyl, preferably hydrogen.

In one embodiment of the compound of formula III R⁴ is hydrogen or C₁₋₆alkyl, preferably hydrogen.

In the above compound of formula III R³ and R⁴ may be taken together toform ═O.

In the above compound of formula III a is preferably 1.

In the above compound of formula III b is preferably 1.

In the above compound of formula III R⁵⁵ and R⁵⁶ are hydrogen, or R⁵⁵and R⁵⁶ may be taken together to form ═O;

c and d are independently 0, 1, or 2, preferably 0 or 1;

c+d is 0, 1, or 2, preferably 1.

In the above compound of formula III R⁵⁷ and R⁵⁸ are independentlyhydrogen or C₁₋₆ -alkyl, preferably hydrogen.

A still further embodiment of the compound of formula I relates to acompound of the general formula IV ##STR35## wherein A¹, D, E, and G¹are defined above;

or a pharmaceutically acceptable salt thereof.

In one embodiment of the compound of formula IV A¹ is

    R.sup.33 --NH--(CR.sup.34 R.sup.35).sub.p.(CH.sub.2).sub.m --M--(CHR.sup.36).sub.o --(CH.sub.2).sub.n --

wherein R³³ is hydrogen or C₁₋₆ alkyl optionally substituted withhydroxyl, preferably hydrogen,

R³⁴ and R³⁵ are independently of each other C₁₋₆ alkyl, preferablymethyl,

M is --CR³⁷ ═CR³⁸ -- or --O--, wherein R³⁷ and R³⁸ are hydrogen or C₁₋₆alkyl, preferably --CH═CH--,

p is 1, m is 1, o is 0 and n is 0.

In another embodiment of the compound of formula IV A¹ is ##STR36##wherein M is --O-- or --S--, preferably --O--, o is 0 or 1, preferably1,

q is 0, 1 or 2, preferably 1, and

m+n is 3 or 4, preferably 3.

In a further embodiment of the compound of formula IV A¹ is ##STR37##wherein R³³ is hydrogen or C₁₋₆ alkyl, preferably, hydrogen, R³⁴ and R³⁵independently of each other are hydrogen or C₁₋₆ alkyl, preferablyhydrogen or methyl,

m is 0 or 1, n is 0 or 1, preferably 0 and p is 0 or 1. In particularthe phenylen moiety is meta-substituted, however it might be ortho- orpara-substituted as well and the invention is by no means limitedhereto.

In the above compound of formula IV A¹ is preferably(1E)-4-amino-4-methylbut-1-enyl, (1E)-4-amino4-methylpent-1-enyl(2-amino-2-methylpropyxy)methyl, ((2S)-pyrrolidin-2-yl)methoxymethyl,4-piperidinyl, (1E)-4-((2R)-2-hydroxypropylamino)-4-methylbut-1-enyl,(1E)-4-((2R)-2-hydroxypropylamino)-4-methylpent-1-enyl,(1E)-4-methyl-4-methylaminopent-1-enyl, 3-(1-aminoethyl)phenyl or3-(aminomethyl)phenyl. In one embodiment hereof A¹ is(1E)-4-amino-4-methylbut-1-enyl, (2-amino-2-methylpropyxy)methyl,((2S)-pyrrolidin-2-yl)methoxymethyl, 4-piperidinyl, or(1E)-4-((2R)-2-hydroxypropylamino)-4-methylbut-1-enyl. In anotherembodiment hereof A¹ is (1E)-4-amino-4-methylpent-1-enyl.

In one embodiment of the compound of formula IV D is ##STR38## whereinR⁵, R⁶, R⁷, R⁸ and R⁹ independently of each other are hydrogen or aryl,prefarably hydrogen or phenyl. More preferred R⁵, R⁶, R⁸ and R⁹ arehydrogen and R⁷ is phenyl.

In a further embodiment of the compound of formula IV D is ##STR39##wherein R⁵ and R⁶ independently of each other are hydrogen or C₁₋₆alkyl, preferably R⁵ and R⁶ are both hydrogen.

In the above compound of formula IV D is preferably (2-naphthyl),benzyloxy, or biphenyl-4-yl. More preferred (2-naphthyl).

In one embodiment of the compound of formula IV E is ##STR40## whereinR¹⁰ and R¹¹ independently of each other are hydrogen or C₁₋₆ alkyl,preferably hydrogen.

In a further embodiment of the compound of formula IV E is ##STR41##wherein R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ independently of each other arehydrogen, --(CH₂)_(v) --NR¹⁵ SO₂ R¹⁷, --(CH₂)_(v) --NR¹⁵ COR¹⁶ or--(CH₂)_(v) --OR¹⁷, wherein v is 0 or 1, preferably 0, R¹⁵ is hydrogenor C₁₋₆ alkyl, preferably hydrogen, R¹⁶ is hydrogen or C₁₋₆ alkyloptionally substituted with --N(R²⁶)R²⁷, wherein R²⁶ and R²⁷independently of each other are hydrogen or C₁₋₆ alkyl, preferably R¹⁶is hydrogen or C₁₋₆ alkyl substituted with amino, R¹⁷ is C₁₋₆ alkyl orphenyl optionally substituted with hydroxyl or phenyl, preferablymethyl, C₁₋₆ alkyl substituted with hydroxyl, e.g. --CH₂ CH₂ OH or --CH₂CH₂ CH₂ OH, or phenyl. In particular the phenylen moiety isortho-substituted, however it may also be meta- or para-substituted andthe invention is by no means limited hereto. In one embodiment, when R¹⁰or R¹⁴ is --(CH₂)_(v) --NR¹⁵ SO₂ R¹⁷, v is 0, R¹⁵ is hydrogen, and R¹⁷is C₁₋₆ alkyl or phenyl, preferably methyl or phenyl. In a secondembodiment, when R¹⁰ or R¹⁴ is --(CH₂)_(v) --NR¹⁵ COR¹⁶, v is 0, R¹⁵ ishydrogen and R¹⁶ is hydrogen or C₁₋₆ alkyl substituted with --NH₂,preferably aminomethyl. In a third embodiment, when R¹⁰ or R¹⁴ is--(CH₂)_(v) --OR¹⁷, v is 0, and R¹⁷ is C₁₋₆ alkyl substituted withhydroxyl, preferably --CH₂ CH₂ OH or --CH₂ CH₂ CH₂ OH.

In the above compound of formula IV E is preferably phenyl, 2-thienyl,2-(2-hydroxyethoxy)phenyl, 2-(3-hydroxypropoxy)phenyl, biphenyl-4-yl,2-(aminoacetylamino)phenyl, 2-(phenylsulfonylamino)phenyl or2-(methylsulfonylamino)phenyl. In one embodiment hereof E is phenyl,2-thienyl or 2-(methylsulfonylamino)phenyl, preferably phenyl.

In one embodiment of the compound of formula IV G¹ is hydrogen or--CONR³⁹ R⁴⁰, wherein R³⁹ and R⁴⁰ independently of each other arehydrogen or C₁₋₆ alkyl, preferably hydrogen or methyl.

In the above compound of formula IV G¹ is preferably hydrogen ormethylcarbamoyl, preferably methylcarbamoyl.

A further embodiment of the compound of formula I relates to a compoundof the general formula V ##STR42## wherein R² is --C(═O)--R⁵⁴ whereinR⁵⁴ is hydrogen or C₁₋₆ -alkyl; and

A¹, D, E, G¹, R¹, R³, and R⁴ are defined above;

or a pharmaceutically acceptable salt thereof.

In one embodiment of the compound of formula II A¹ is

    R.sup.33 --NH--(CR.sup.34 R.sup.35).sub.p.(CH.sub.2).sub.m --M--(CHR.sup.36).sub.o --(CH.sub.2).sub.n --

wherein R³³ is hydrogen or C₁₋₆ alkyl optionally substituted withhydroxyl, preferably hydrogen, methyl or hydroxypropyl, e.g.(2R)-2-hydroxypropyl,

R³⁴ and R³⁵ are independently of each other C₁₋₆ alkyl, preferablymethyl,

R³⁶ is hydrogen,

M is --CR³⁷ ═CR³⁸ -- or --O--, wherein R³⁷ and R³⁸ are hydrogen or C₁₋₆alkyl, preferably --CH═CH-- or O,

p is 1, m is 1, o is 0or 1 and n is 0 or 1.

In another embodiment of the compound of formula II A¹ is ##STR43##wherein M is --O-- or --S--, preferably --O--, o is 0 or 1, preferably1,

q is 0, 1 or 2, preferably 1, and

m+n is 3 or 4, preferably 3.

In a further embodiment of the compound of formula V A¹ is ##STR44##wherein R³³ is hydrogen or C₁₋₆ alkyl, preferably, hydrogen, R³⁴ and R³⁵independently of each other are hydrogen or C₁₋₆ alkyl, preferablyhydrogen or methyl,

m is 0 or 1, n is 0 or 1, preferably 0 and p is 0 or 1. In particularthe phenylen moiety is meta-substituted, however it might be ortho- orpara-substituted as well and the invention is by no means limitedhereto.

In the above compound of formula V A¹ is preferably(1E)-4-amino-4-methylbut-1-enyl, (1E)-4-amino4-methylpent-1-enyl(2-amino-2-methylpropyxy)methyl, ((2S)-pyrrolidin-2-yl)methoxymethyl,4-piperidinyl, (1E)-4-((2R)-2-hydroxypropylamino)-4-methylbut-1-enyl,(1E)-4-((2R)-2-hydroxypropylamino)-4-methylpent-1-enyl,(1E)-4-methyl-4-methylaminopent-1-enyl 3-(1-aminoethyl)phenyl or3-(aminomethyl)phenyl. In one embodiment hereof A¹ is preferably(1E)-4-amino-4-methylbut-l-enyl, (2-amino-2-methylpropyxy)methyl,((2S)-pyrrolidin-2-yl)methoxymethyl, 4-piperidinyl, or(1E)-4-((2R)-2-hydroxypropylamino)-4-methylbut-1-enyl.

In one embodiment of the compound of formula V D is ##STR45## whereinR⁵, R⁶, R⁷, R⁸ and R⁹ independently of each other are hydrogen or aryl,prefarably hydrogen or phenyl. More preferred R⁵, R⁶, R⁸ and R⁹ arehydrogen and R⁷ is phenyl.

In a further embodiment of the compound of formula V D is ##STR46##wherein R⁵ and R⁶ independently of each other are hydrogen or C₁₋₆alkyl, preferably hydrogen.

In the above compound of formula V D is preferably (2-naphthyl),benzyloxy, or biphenyl-4-yl. More preferred (2-naphthyl) orbiphenyl-4-yl.

In one embodiment of the compound of formula V E is ##STR47## whereinR¹⁰ and R¹¹ independently of each other are hydrogen or C₁₋₆ alkyl,preferably hydrogen.

In a further embodiment of the compound of formula V E is ##STR48##wherein R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ independently of each other arehydrogen, --(CH₂)_(v) --NR¹⁵ SO₂ R¹⁷, --(CH₂)_(v) --NR¹⁵ COR¹⁶ or--(CH₂)_(v) --OR¹⁷, wherein v is 0 or 1, preferably 0, R¹⁵ is hydrogenor C₁₋₆ alkyl, preferably hydrogen, R¹⁶ is hydrogen or C₁₋₆ alkyloptionally substituted with --N(R²⁶)R²⁷, wherein R²⁶ and R²⁷independently of each other are hydrogen or C₁₋₆ alkyl, preferably R¹⁶is hydrogen or C₁₋₆ alkyl substituted with amino, R¹⁷ is C₁₋₆ alkyl orphenyl optionally substituted with hydroxyl or phenyl, preferablymethyl, C,₁₋₆ alkyl substituted with hydroxyl, e.g. --CH₂ CH₂ OH or--CH₂ CH₂ CH₂ OH, or phenyl. In particular the phenylen moiety isortho-substituted, however it may also be meta- or para-substituted andthe invention is by no means limited hereto. In one embodiment, when R¹⁰or R¹⁴ is --(CH₂)_(v) --NR¹⁵ SO₂ R¹⁷, v is 0, R¹⁵ is hydrogen, and R¹⁷is C₁₋₆ alkyl or phenyl, preferably methyl or phenyl. In a secondembodiment, when R¹⁰ or R¹⁴ is --(CH₂)_(v) --NR¹⁵ COR⁶, v is 0, R¹⁵ ishydrogen and R¹⁶ is hydrogen or C₁₋₆ alkyl substituted with --NH₂,preferably aminomethyl. In a third embodiment, when R¹⁰ or R¹⁴ is--(CH₂)_(v) --OR¹⁷, v is 0, and R¹⁷ is C₁₋₆ alkyl substituted withhydroxyl, preferably --CH₂ CH₂ OH or --CH₂ CH₂ CH₂ OH.

In the above compound of formula II E is preferably phenyl, 2-thienyl,2-(2-hydroxyethoxy)phenyl, 2-(3-hydroxypropoxy)phenyl, biphenyl-4-yl,2-(aminoacetylamino)phenyl, 2-(phenylsulfonylamino)phenyl or2-(methylsulfonylamino)phenyl. In one embodiment hereof E is phenyl,2-thienyl or 2-(methylsulfonylamino)phenyl, preferably phenyl, or2-thienyl.

In one embodiment of the compound of formula V G¹ is hydrogen or--CONR³⁹ R⁴⁰, wherein R³⁹ and R⁴⁰ independently of each other arehydrogen or C₁₋₆ alkyl, preferably hydrogen, methyl or ethyl.

In the above compound of formula V G¹ is preferably hydrogen, methyl,methylcarbamoyl, or ethylcarbamoyl.

In one embodiment of the compound of formula V R¹ is C₁₋₆ alkyl,preferably hydrogen or C₁₋₄ alkyl.

In the above compound of formula V R¹ is preferably hydrogen or methyl,most preferred hydrogen.

In one embodiment of the compound of formula V R² is --C(═O)--R⁵⁴,wherein R⁵⁴ is C₁₋₄ alkyl, preferably --C(═O)--CH₃.

In one embodiment of the compound of formula V R³ is hydrogen or C₁₋₆alkyl, preferably hydrogen.

In one embodiment of the compound of formula V R⁴ is hydrogen or C₁₋₆alkyl, preferably hydrogen.

A still further embodiment of the compound of formula I relates to acompound of the general formula VI ##STR49## wherein A², D, E, G², R¹,R², R³, R⁴, and b are defined above;

or a pharmaceutically acceptable salt thereof.

In one embodiment of the compound of formula VI A² is

    R.sup.33 --NH--(CR.sup.34 R.sup.35).sub.p.(CH.sub.2).sub.m --M--(CHR.sup.36).sub.o --(CH.sub.2).sub.n --

wherein R³³ is hydrogen or C₁₋₆ alkyl optionally substituted withhydroxyl, preferably hydrogen, methyl or hydroxypropyl, e.g.(2R)-2-hydroxypropyl,

R³⁴ and R³⁵ are independently of each other C₁₋₆ alkyl, preferablymethyl,

M is --CR³⁷ ═CR³⁸ -- or --O--, wherein R³⁷ and R³⁸ are hydrogen or C₁₋₆alkyl, preferably --CH═CH--,

p is 1, m is 1, O is 0 and n is 0 or 1, preferably 0.

In another embodiment of the compound of formula VI A² is ##STR50##wherein M is --O-- or --S--, preferably --O--, o is 0 or 1, preferably1,

q is 0, 1 or 2, preferably 1, and

m+n is 3 or 4, preferably 3.

In a further embodiment of the compound of formula VI A² is ##STR51##wherein R³³ is hydrogen or C₁₋₆ alkyl, preferably, hydrogen, R³⁴ and R³⁵independently of each other are hydrogen or C₁₋₆ alkyl, preferablyhydrogen or methyl,

m is 0 or 1, n is 0 or 1, preferably 0 and p is 0 or 1. In particularthe phenylen moiety is meta-substituted, however it might be ortho- orpara-substituted as well and the invention is by no means limitedhereto.

In the above compound of formula VI A² is preferably(1E)-4-amino-4-methylbut-1-enyl, (1E)-4-amino-4-methylpent-1-enyl(2-amino-2-methylpropyxy)methyl, ((2S)-pyrrolidin-2-yl)methoxymethyl,4-piperidinyl, (1E)-4-((2R)-2-hydroxypropylamino)-4-methylbut-1-enyl,(1E)-4-((2R)-2-hydroxypropylamino)-4-methylpent-1-enyl,(1E)-4-methyl-4-methylaminopent-1-enyl, 3-(1-aminoethyl)phenyl or3-(aminomethyl)phenyl. In one embodiment hereof A² is(1E)-4-amino-4-methylbut-1-enyl, (2-amino-2-methylpropoxy)methyl,((2S)-pyrrolidin-2-yl)methoxymethyl, 4-piperidinyl or(1E)-4-((2R)-2-hydroxypropylamino)-4-methylbut-1-enyl. In anotherembodiment hereof A² is (1E)-4-amino-4-methylpent-1-enyl, 4-piperidinylor (1E)-4-((2R)-2-hydroxypropylamino)-4-methylbut-1-enyl.

In one embodiment of the compound of formula VI D is ##STR52## whereinR⁵, R⁶, R⁷, R⁸ and R⁹ independently of each other are hydrogen or aryl,prefarably hydrogen or phenyl. More preferred R⁵, R⁶, R⁸ and R⁹ arehydrogen and R⁷ is phenyl.

In a further embodiment of the compound of formula VI D is ##STR53##wherein R⁵ and R⁶ independently of each other are hydrogen or C₁₋₆alkyl, preferably R⁵ and R⁶ are both hydrogen.

In the above compound of formula VI D is preferably (2-naphthyl),benzyloxy, or biphenyl-4-yl. More preferred (2-naphthyl) orbiphenyl-4-yl, most preferred 2-naphthyl.

In one embodiment of the compound of formula VI E is ##STR54## whereinR¹⁰ and R¹¹ independently of each other are hydrogen or C₁₋₆ alkyl,preferably hydrogen.

In a further embodiment of the compound of formula VI E is ##STR55##wherein R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ independently of each other arehydrogen, --(CH₂)_(v) --NR¹⁵ SO₂ R¹⁷, --(CH₂)_(v) --NR¹⁵ COR¹⁶ or--(CH₂)_(v) --OR¹⁷, wherein v is 0 or 1, preferably hydrogen or C₁₋₆alkyl, preferably hydrogen, R¹⁶ is hydrogen or C₁₋₆ alkyl optionallysubstituted with --N(R²)R²⁷, wherein R²⁶ and R²⁷ independently of eachother are hydrogen or C₁₋₆ alkyl, preferably R¹⁶ is hydrogen or C₁₋₆alkyl substituted with amino, R¹⁷ is C₁₋₆ alkyl or phenyl optionallysubstituted with hydroxyl or phenyl, preferably methyl, C₁₋₆ alkylsubstituted with hydroxyl, e.g. --CH₂ CH₂ OH or -CH₂ CH₂ CH₂ OH, orphenyl. In particular the phenylen moiety is ortho-substituted, howeverit may also be meta- or para-substituted and the invention is by nomeans limited hereto. In one embodiment, when R¹⁰ or R¹⁴ is --(CH₂)_(v)--NR¹⁵ SO₂ R¹⁷, v is 0, R¹⁵ is hydrogen, and R¹⁷ is C₁₋₆ alkyl orphenyl, preferably methyl or phenyl. In a second embodiment, when R¹⁰ orR¹⁴ is --(CH₂)_(v) --NR¹⁵ COR¹⁶, v is 0, R¹⁵ is hydrogen and R¹ ishydrogen or C₁₋₆ alkyl substituted with --NH₂, preferably aminomethyl.In a third embodiment, when R¹⁰ or R¹⁴ is --(CH₂)_(v) --OR¹⁷, v is 0,and R¹⁷ is C₁₋₆ alkyl substituted with hydroxyl, preferably --CH₂ CH₂ OHor --CH₂ CH₂ CH₂ OH.

In the above compound of formula I E is preferably phenyl, 2-thienyl,2-(2-hydroxyethoxy)phenyl, 2-(3-hydroxypropoxy)phenyl, biphenyl4-yl,2-(aminoacetylamino)phenyl, 2-(phenylsulfonylamino)phenyl or2-(methylsulfonylamino)phenyl. In one embodiment hereof E is phenyl,2-thienyl or 2-(methylsulfonylamino)phenyl.

In one embodiment of the compound of formula VI G² is hydrogen or C₁₋₄alkyl, preferably hydrogen, methyl or ethyl. In the above compound offormula VI G² is preferably hydrogen or methyl.

In one embodiment of the compound of formula VI R¹ is hydrogen or C₁₋₆alkyl, preferably hydrogen or C₁₋₄ alkyl.

In the above compound of formula VI R¹ is preferably methyl.

In one embodiment of the compound of formula VI R² is hydrogen,--C(═O)--R⁵⁴ or C₁₋₆ alkyl, wherein R⁵⁴ is C₁₋₆ alkyl, preferablyhydrogen, C₁₋₆ alkyl or --C(═O)--CH₃.

In the above compound of formula VI R² is preferably methyl, hydrogen,or acetyl, most preferred methyl.

In one embodiment of the compound of formula VI R³ is hydrogen or C₁₋₆alkyl, preferably hydrogen.

In one embodiment of the compound of formula VI R⁴ is hydrogen or C₁₋₆alkyl, preferably hydrogen.

In the above compound of formula VI R³ and R⁴ may be taken together toform ═O.

In the above compound of formula VI b is preferably 0 or 1, mostpreferred 1.

A further embodiment of the compound of formula I relates to a compoundof the general formula VII ##STR56## wherein E is hydrogen,--O--(CH₂)_(l) --R^(10a), ##STR57## wherein R¹⁰, R¹¹, R¹², R¹³ and R¹⁴independently are hydrogen, halogen, aryl, C₁₋₆ -alkyl, C₁₋₆ -alkoxy;

R^(10a) is hydrogen, aryl optionally substituted with halogen or C₁₋₆-alkyl, or C₁₋₆ -alkyl optionally substituted with halogen or C₁₋₆-alkyl, and

l is 0, 1, 2, or 3;

and A¹, D, G¹, R¹, R², a, and b are defined above;

or a pharmaceutically acceptable salt thereof.

In one embodiment of the compound of formula VII A¹ is

    R.sup.33 --NH--(CR.sup.34 R.sup.35).sub.p.(CH.sub.2).sub.m --M--(CHR.sup.36).sub.o --(CH.sub.2).sub.n --

wherein R³³ is hydrogen or C₁₋₆ alkyl optionally substituted withhydroxyl, preferably hydrogen or methyl, most preferred hydrogen,

R³⁴ and R³⁵ are independently of each other C₁₋₆ alkyl, preferablymethyl,

R³⁶ is hydrogen,

M is --CR³⁷ ═CR³⁸ -- or --O--, wherein R³⁷ and R³⁸ are hydrogen or C₁₋₆alkyl, preferably --CH═CH-- or

O,

p is 1, m is 1, o is 0 or 1 and n is 0 or 1.

In another embodiment of the compound of formula VII A¹ is ##STR58##wherein M is --O-- or --S--, preferably --O--, o is 0 or 1, preferably1,

q is 0, 1 or 2, preferably 1, and

m+n is 3 or 4, preferably 3.

In a further embodiment of the compound of formula VII A¹ is ##STR59##wherein R³³ is hydrogen or C₁₋₆ alkyl, preferably, hydrogen, R³⁴ and R³⁵independently of each other are hydrogen or C₁₋₆ alkyl, preferablyhydrogen or methyl,

m is 0 or 1, n is 0 or 1, preferably 0 and p is 0 or 1. In particularthe phenylen moiety is meta-substituted, however it might be ortho- orpara-substituted as well and the invention is by no means limitedhereto.

In the above compound of formula VII A¹ is preferably(1E)-4-amino-4-methylbut-1-enyl, (1E)-4-amino-4-methylpent-1-enyl(2-amino-2-methylpropyxy)methyl, ((2S)-pyrrolidin-2-yl)methoxymethyl,4-piperidinyl, (1E)-4-((2R)-2-hydroxypropylamino)4-methylbut-1-enyl,(1E)-4-((2R)-2-hydroxypropylamino)4-methylpent-1-enyl,(1E)-4-methyl-4-methylaminopent-1-enyl, 3-(1-aminoethyl)phenyl or3-(aminomethyl)phenyl. In one embodiment hereof A¹ is(1E)-4-amino-4-methylbut-1-enyl, (2-amino-2-methylpropyxy)methyl,((2S)-pyrrolidin-2-yl)methoxymethyl, 4-piperidinyl, or(1E)-4-((2R)-2-hydroxypropylamino)-4-methylbut-1-enyl. In anotherembodiment hereof A¹ is (1E)-4-amino-4-methylpent-1-enyl,(2-amino-2-methylpropoxy)methyl or ((2S)-pyrrolidin-2-yl)methoxymethyl.

In one embodiment of the compound of formula VII D is ##STR60## whereinR⁵, R⁶, R⁷, R⁸ and R⁹ independently of each other are hydrogen or aryl,prefarably hydrogen or phenyl. More preferred R⁵, R⁶, R⁸ and R⁹ arehydrogen and R⁷ is phenyl.

In a further embodiment of the compound of formula VII D is ##STR61##wherein R⁵ and R⁶ independently of each other are hydrogen or C₁₋₆alkyl, preferably R⁵ and R⁶ are both hydrogen.

In the above compound of formula VII D is preferably (2-naphthyl),benzyloxy, or biphenyl-4-yl. More preferred (2-naphthyl) orbiphenyl-4-yl, most preferred 2-naphthyl.

In one embodiment of the compound of formula VII E is ##STR62## whereinR¹⁰ and R¹¹ independently of each other are hydrogen or C₁₋₆ alkyl,preferably hydrogen.

In a further embodiment of the compound of formula VII E is ##STR63##wherein R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ independently of each other arehydrogen, --(CH₂)_(v) --NR¹⁵ SO₂ R¹⁷, --(CH₂)_(v) --NR¹⁵ COR¹⁶ or--(CH₂)_(v) --OR¹⁷, wherein v is 0 or 1, preferably 0, R¹⁵ is hydrogenor C₁₋₆ alkyl, preferably hydrogen, R¹⁶ is hydrogen or C₁₋₆ alkyloptionally substituted with --N(R²⁶)R²⁷, wherein R²⁶ and R²⁷independently of each other are hydrogen or C₁₋₆ alkyl, preferably R¹⁶is hydrogen or C₁₋₆ alkyl substituted with amino, R¹⁷ is C₁₋₆ alkyl orphenyl optionally substituted with hydroxyl or phenyl, preferablymethyl, C₁₋₆ alkyl substituted with hydroxyl, e.g. --CH₂ CH₂ OH or --CH₂CH₂ CH₂ OH, or phenyl. In particular the phenylen moiety isortho-substituted, however it may also be meta- or para-substituted andthe invention is by no means limited hereto. In one embodiment, when R¹⁰or R¹⁴ is --(CH₂)_(v) --NR¹⁵ SO₂ R⁷, v is 0, R¹⁵ is hydrogen, and R¹⁷ isC₁₋₆ alkyl or phenyl, preferably methyl or phenyl. In a secondembodiment, when R¹⁰ or R¹⁴ is --(CH₂)_(v) --NR¹⁵ COR¹⁶, v is 0, R¹⁵ ishydrogen and R¹⁶ is hydrogen substituted with --NH₂, preferablyaminomethyl. In a third embodiment, when R¹⁰ or R¹⁴ is --(CH₂)_(v)--OR¹⁷, v is 0, and R¹⁷ is C₁₋₆ alkyl substituted with hydroxyl,preferably --CH₂ CH₂ OH or --CH₂ CH₂ CH₂ OH.

In the above compound of formula VII E is preferably phenyl, 2-thienyl,2-(2-hydroxyethoxy)phenyl, 2-(3-hydroxypropoxy)phenyl, biphenyl-4-yl,2-(aminoacetylamino)phenyl, 2-(phenylsulfonylamino)phenyl or2-(methylsulfonylamino)phenyl. In one embodiment hereof E is preferablyphenyl, or 2-thienyl, most preferred phenyl.

In one embodiment of the compound of formula VII G¹ is hydrogen or--CONR³⁹ R⁴⁰, wherein R³⁹ and R⁴⁰ independently of each other arehydrogen or C₁₋₆ alkyl, preferably hydrogen, methyl or ethyl.

In the above compound of formula VII G¹ is preferably methylcarbamoyl orethylcarbamoyl, most preferred ethylcarbamoyl.

In one embodiment of the compound of formula VII R¹ is C₁₋₆ alkyl,preferably hydrogen or C₁₋₄ alkyl. In the above compound of formula VIIR¹ is preferably methyl.

In one embodiment of the compound of formula VII R² is hydrogen,--C(═O)--R⁵⁴ or C₁₋₆ alkyl, wherein R⁵⁴ is C₁₋₆ alkyl, preferablyhydrogen, C₁₋₆ alkyl or --C(═O)--CH₃.

In the above compound of formula VII R² is preferably methyl, hydrogen,or acetyl, more preferred methyl or hydrogen, most preferred hydrogen.

In the above compound of formula VII a is preferably 1.

In the above compound of formula VII b is preferably 1.

The compounds of formulas I-VII comprise any optical isomers thereof, inthe form of separated, pure or partially purified optical isomers orracemic mixtures thereof.

Preferred compounds of the invention are:

1-((2R)-2-(N-((2E)-5-amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-2-benzyl-4-ethylsemicarbazide:##STR64##(2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionicacid N-methyl-N-phenethylamide: ##STR65##1-((2R)-2-(N-(2-(((2S)-pyrrolidin-2yl)methoxy)acetyl)-N-methylamino)-3-(2-naphthyl)propionyl)-2-benzyl-4-ethylsemicarbazide:##STR66##1-((2R)-2-(N-((2-amino-2-methylpropoxy)acetyl)-N-methylamino)-3-(2-naphthyl)propionyl)-2-benzyl-4-ethylsemicarbazide:##STR67##(2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionicacid N-methyl-N-(2-(2-(methylsulfonylamino)phenyl)ethyl)amide: ##STR68##(2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionicacid N-methyl-N-(2-(2-thienyl)ethyl)amide: ##STR69##(2R)-2-((5R)-4-((2E)-5-Amino-5-methylhex-2-enoyl)-5-(2-naphthyl)methyl-2-oxopiperazin-1-yl)-N-methyl-3-phenylpropionamide:##STR70##(2R)-2-(N-((2E)-5-((2R)-2-hydroxypropylamino)-5-methylhex-2-enoyl)-N-methylamino)-N-methyl-3-(2-naphthyl)-N-phenethylpropionamide:##STR71## (2E)-5-Amino-5-methylhex-2-enoic acidN-((1R)-2-(N-acetyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)amino)-1-((2-naphthyl)methyl)ethyl)amide:##STR72##(2E)-5-Amino-5-methyl-N-methyl-N-((1R)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)hex-2-enamide##STR73##(2E)-5-Methyl-5-(methylamino)-N-methyl-N-((1R)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)hex-2-enamide##STR74## (2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-(N-methyl-N-(3-phenylpropyl)carbamoyl)-2-(2-naphthyl)ethyl)amide##STR75##(2R)-2-(N-(3-(1-Aminoethyl)benzoyl)-N-methylamino)-N-methyl-3-(2-naphthyl)-N-(2-(2-thienyl)ethyl)propionamide##STR76## (2E)-5-Amino-5-methylhex-2-enoic acidN-((1R)-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1-((2-naphthyl)methyl)-2-oxoethyl)-N-methylamide##STR77##(2E)-5-Methyl-N-methyl-5-(methylamino)-N-((1R)-1-(N-methyl-N-phenethylcarbamoyl)-2-(2-naphthyl)ethyl)hex-2-enamide##STR78##(2R)-2-(N-((2E)-5-Amino-5-methyihex-2-enoyl)-N-methylamino)-N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methyl-3-(2-naphthyl)propionamide##STR79##(2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-N-methyl-3-(2-naphthyl)-N-(2-(2-methylsulfonylaminophenyl)ethyl)propionamide##STR80##(2E)-5-Amino-N-((1R)-2-(biphenyl-4-yl)-1-(N-(2-(2-thienyl)ethyl)-5-methyl-N-methylhex-2-enamide##STR81##(2E)-N-((1R)-1-(N-(2-(2-(2-Hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methyl-5-methyl-5-(methylamino)hex-2-enamide##STR82## 3-Aminomethyl-N- (1R)-1-(N-{2-2-(2-hydroxyethoxy)phenyl!ethyl}-N-methylcarbamoyl)-2-(2-naphthyl)ethyl!benzamide##STR83## (2E)-5-Amino-5-methylhex-2-enoic acidN-((1R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl-N-methylcarbomoyl)-2-(2-naphthyl)ethyl)amide##STR84## (2E)-5-Amino-5-methylhex-2-enoic acid N-((1R)-1-{N-2-(2-(benzensulfonylamino)phenyl)ethyl!-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide##STR85##2-Amino-N-(2-(2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)ethyl)phenyl)acetamide##STR86##(2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-N-(2-(2-(3-hydroxypropoxy)phenyl)ethyl)-N-methyl-3-(2-naphthyl)propionamide##STR87## 3-Aminomethyl-N- (1R)-1-(N-{2-2-(2-hydroxyethoxy)phenyl!ethyl}-N-methylcarbamoyl)-2-(2-naphthyl)ethyl!benzamide##STR88## (2E)-5-Amino-5-methylhex-2-enoic acidN-((1R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methylcarbomoyl)-2-(2-naphthyl)ethyl)-N-methylamide##STR89## (3R)-4-((2E)-5-Amino-5-methylhex-2-enoyl)-3-((2-naphthyl)methyl)-1-phenethylpiperanzin-2-one##STR90##

Throughout the present specification compounds of formula I are alsointended to comprise compounds of formula II, III, IV, V, VI, and VII,and thus, a reference to formula I is also a reference to any one offormula II, III, IV, V, VI, and VII.

It is believed that compounds of formula I exhibit an improvedresistance to proteolytic degradation by enzymes compared to that of thepeptides suggested in the prior literature, due to the lack of naturalpeptide bonds. The increased resistance to proteolytic degradationcombined with the reduced size of the compounds of the invention incomparison with known growth hormone releasing peptides is expected toimprove their bioavailability compared to that of the peptides suggestedin the prior literature.

In the above structural formulas and throughout the presentspecification, the following terms have the indicated meanings:

The C₁₋₆ alkyl groups specified above are intended to include thosealkyl groups of the designated length in either a linear or branched orcyclic configuration. Examples of linear alkyl are methyl, ethyl,propyl, butyl, pentyl, and hexyl. Examples of branched alkyl areisopropyl, sec-butyl, tert-butyl, isopentyl, and isohexyl. Examples ofcyclic alkyl are C₃₋₆ -cycloalkyl such as cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

The C₁₋₆ -alkoxy groups specified above are intended to include thosealkoxy groups of the designated length in either a linear or branched orcyclic configuration. Examples of linear alkyloxy are methoxy, ethoxy,propoxy, butoxy, pentoxy, and hexoxy. Examples of branched alkoxy areisopropoxy, sec-butoxy, tert-butoxy, isopentoxy, and isohexoxy. Examplesof cyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy andcyclohexyloxy.

In the present context, the term "aryl" is intended to include aromaticrings, such as carbocyclic and heterocyclic aromatic rings selected fromthe group consisting of phenyl, naphthyl, pyridyl, 1-H-tetrazol-5-yl,thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiopheneyl, quinolinyl, pyrazinyl,or isothiazolyl, optionally substituted by one or more C₁₋₆ -alkyl, C₁₋₆-alkoxy, halogen, amino or aryl. Aryl is preferably phenyl, thienyl,imidazolyl, oxadiazolyl, pyridyl, indolyl, quinolinyl or naphthyloptionally substituted with halogen, amino, hydroxy, C₁₋₆ -alkyl or C₁₋₆-alkoxy.

The term "halogen" is intended to include Cl, F, Br and I.

The compounds of the present invention may have one or more asymmetriccenters and it is intended that stereoisomers, as separated, pure orpartially purified stereoisomers or racemic mixtures thereof areincluded in the scope of the invention. The compounds of the presentinvention may optionally be on a pharmaceutically acceptable salt formsuch as the pharmaceutically acceptable acid addition salts of compoundsof formula I which include those prepared by reacting the compound offormula I with an inorganic or organic acid such as hydrochloric,hydrobromic, sulfuric, acetic, phosphoric, lactic, maleic, phthalic,citric, glutaric, gluconic, methanesulfonic, salicylic, succinic,tartaric, toluenesulfonic, trifluoracetic, sulfamic or fumaric acid.

The compounds of formula I may be administered in pharmaceuticallyacceptable acid addition salt form or, where appropriate, as a alkalimetal or alkaline earth metal or lower alkylammonium salt. Such saltforms are believed to exhibit approximately the same order of activityas the free base forms.

In another aspect, the present invention relates to a pharmaceuticalcomposition comprising, as an active ingredient, a compound of thegeneral formula I or a pharmaceutically acceptable salt thereof togetherwith a pharmaceutically acceptable carrier or diluent.

Pharmaceutical compositions containing a compound of the presentinvention may be prepared by conventional techniques, e.g. as describedin Remington's Pharmaceutical Sciences, 1985. The compositions mayappear in conventional forms, for example capsules, tablets, aerosols,solutions, suspensions or topical applications.

The pharmaceutical carrier or diluent employed may be a conventionalsolid or liquid carrier. Examples of solid carriers are lactose, terraalba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia,magnesium stearate, stearic acid or lower alkyl ethers of cellulose.Examples of liquid carriers are syrup, peanut oil, olive oil,phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water.

Similarly, the carrier or diluent may include any sustained releasematerial known in the art, such as glyceryl monostearate or glyceryldistearate, alone or mixed with a wax.

If a solid carrier is used for oral administration, the preparation maybe tabletted, placed in a hard gelatin capsule in powder or pellet formor it can be in the form of a troche or lozenge. The amount of solidcarrier will vary widely but will usually be from about 25 mg to about 1g. If a liquid carrier is used, the preparation may be in the form of asyrup, emulsion, soft gelatin capsule or sterile injectable liquid suchas an aqueous or non-aqueous liquid suspension or solution.

A typical tablet which may be prepared by conventional tablettingtechniques may contain:

    ______________________________________    Core:    Active compound (as free compound or salt thereof)                               100    mg    Colloidal silicon dioxide (Aerosil)                               1.5    mg    Cellulose, microcryst. (Avicel)                               70     mg    Modified cellulose gum (Ac-Di-Sol)                               7.5    mg    Magnesium stearate    Coating:    HPMC approx.               9      mg    *Mywacett 9-40 T approx.   0.9    mg    ______________________________________     *Acylated monoglyceride used as plasticizer for film coating.

For nasal administration, the preparation may contain a compound offormula I dissolved or suspended in a liquid carrier, in particular anaqueous carrier, for aerosol application. The carrier may containadditives such as solubilizing agents, e.g. propylene glycol,surfactants, absorption enhancers such as lecithin (phosphatidylcholine)or cyclodextrin, or preservatives such as parabenes.

Generally, the compounds of the present invention are dispensed in unitdosage form comprising 50-200 mg of active ingredient together with apharmaceutically acceptable carrier per unit dosage. The dosage of thecompounds according to this invention is suitably 0.1-500 mg/day, e.g.from about 5 to about 50 mg, such as about 10 mg per dose, whenadministered to patients, e.g. humans, as a drug.

It has been demonstrated that compounds of the general formula I possessthe ability to release endogenous growth hormone in vivo. The compoundsmay therefore be used in the treatment of conditions which requireincreased plasma growth hormone levels such as in growth hormonedeficient humans or in elderly patients or livestock.

Thus, in a particular aspect, the present invention relates to apharmaceutical composition for stimulating the release of growth hormonefrom the pituitary, the composition comprising, as an active ingredient,a compound of the general formula I or a pharmaceutically acceptablesalt thereof together with a pharmaceutically acceptable carrier ordiluent.

In a further aspect, the present invention relates to a method ofstimulating the release of growth hormone from the pituitary, the methodcomprising administering to a subject in need thereof an effectiveamount of a compound of the general formula I or a pharmaceuticallyacceptable salt thereof.

In a still further aspect, the present invention relates to the use of acompound of the general formula I or a pharmaceutically acceptable saltthereof for the preparation of a medicament for stimulating the releaseof growth hormone from the pituitary.

To those skilled in the art, it is well known that the current andpotential uses of growth hormone in humans are varied and multitudinous.Thus, compounds of formula I can be administered for purposesstimulating release of growth hormone from the pituitary and would thenhave similar effects or uses as growth hormone itself. The uses ofgrowth hormone may be summarized as follows: stimulation of growthhormone release in the elderly; prevention of catabolic side effects ofglucocorticoids, prevention and treatment of osteoporosis, treatment ofNIDDM, stimulation of the immune system, acceleration of wound healing,accelerating bone fracture repair, treatment of growth retardation,treating renal failure or insufficiency resulting from growthretardation, treatment of physiological short stature including growthhormone deficient children and short stature associated with chronicillness, treatment of obesity and growth retardation associated withobesity, treatment of anorexia, treating growth retardation associatedwith the Prader-Willi syndrome and Turner's syndrome; accelerating therecovery and reducing hospitalization of burn patients; treatment ofintrauterine growth retardation, skeletal dysplasia, hypercortisolismand Cushing's syndrome; induction of pulsatile growth hormone release;replacement of growth hormone in stressed patients, treatment ofosteochondrodysplasias, Noonan's syndrome, schizophrenia, depressions,Alzheimer's disease, delayed wound healing and psychosocial deprivation,treatment of pulmonary dysfunction and ventilator dependency,attenuation of protein catabolic responses after major surgery, reducingcachexia and protein loss due to chronic illness such as cancer or AIDS;treatment of hyperinsulinemia including nesidioblastosis, adjuvanttreatment for ovulation induction; to stimulate thymic development andprevent the age-related decline of thymic function, treatment ofimmunosuppressed patients, improvement in muscle strength, mobility,maintenance of skin thickness, metabolic homeostasis, renal homeostasisin the frail elderly, stimulation of osteoblasts, bone remodelling andcartilage growth, stimulation of the immune system in companion animalsand treatment of disorder of aging in companion animals, growth promoterin livestock and stimulation of wool growth in sheep.

For the above indications the dosage will vary depending on the compoundof formula I employed, on the mode of administration and on the therapydesired. However, generally dosage levels between 0.0001 and 100 mg/kgbody weight daily are administered to patients and animals to obtaineffective release of endogenous growth hormone. Usually, dosage formssuitable for oral, nasal, pulmonal or transdermal administrationcomprise from about 0.0001 mg to about 100 mg, preferably from about0.001 mg to about 50 mg of the compounds of formula I admixed with apharmaceutically acceptable carrier or diluent.

Optionally, the pharmaceutical composition of the invention may comprisea compound of formula I combined with one or more compounds exhibiting adifferent activity, e.g., an antibiotic or other pharmacologicallyactive material.

The route of administration may be any route which effectivelytransports the active compound to the appropriate or desired site ofaction, such as oral, nasal, pulmonary, transdermal or parenteral, theoral route being preferred.

Apart from the pharmaceutical use of the compounds of formula 1, theymay be useful in vitro tools for investigating the regulation of growthhormone release.

Compounds of formula I may also be useful in vivo tools for evaluatingthe growth hormone releasing capability of the pituitary. For example,serum samples taken before and after administration of these compoundsto humans can be assayed for growth hormone. Comparison of the growthhormone in each serum sample would directly determine the ability of thepatients pituitary to release growth hormone.

Compounds of formula I may be administered to commercially importantanimals, such as cows, sheeps, pigs, goats, etc. to increase their rateand extent of growth, and to increase milk production.

A further use of growth hormone secretagogue compounds of formula I isin combination with other secretagogues such as GHRP (2 or 6), GHRH andits analogues, growth hormone and its analogues or somatomedinsincluding IGF-1 and IGF-2.

Pharmacological Methods

Compounds of formula I may be evaluated in vitro for their efficacy andpotency to release growth hormone in rat pituitary primary cultures.

The isolation of rat pituitary cells is a modification of O. Sartor etal., Endocrinology 116, 1985, pp. 952-957. Male albino Sprague-Dawleyrats (250+/-25 grams) were purchased from M.o slashed.llegaard, LilleSkensved, Denmark. The rats were housed in group cages (fouranimals/cage) and placed in rooms with 12 hour light cycle. The roomtemperature varied from 19-24° C. and the humidity from 30-60%.

The rats were decapitated and the pituitaries dissected. Theneurointermediate lobes were removed and the remaining tissue wasimmediately placed in icecold isolation buffer (Gey's medium (Gibco041-04030) supplemented with 0.25% D-glucose, 2% non-essential aminoacids (Gibco 043-01140) and 1% bovine serum albumine (BSA) (SigmaA-4503)). The tissue was cut into small pieces and transferred toisolation buffer supplemented with 3.8 mg/ml of trypsin (Worthington#3707 TRL-3) and 330 mg/ml of DNase (Sigma D-4527). This mixture wasincubated at 70 rotations/min for 35 min at 37° C. in a 95/5% atmosphereof O₂ /CO₂. The tissue was then washed three times in the above buffer.Using a standard pasteur pipette, the tissue was then aspirated intosingle cells. After dispersion, cells were filtered through a nylonfilter (160 mm) to remove undigested tissue. The cell suspension waswashed 3 times with isolation buffer supplemented with trypsin inhibitor(0.75 mg/ml, Worthington #2829) and finally resuspended in culturemedium; DMEM (Gibco 041-01965) supplemented with 25 mM HEPES (SigmaH-3375), 4 mM glutamine (Gibco 043-05030H), 0.075% sodium bicarbonate(Sigma S-8875), 0.1% non-essential amino acid, 2.5% fetal calf serum(FCS, Gibco 011-06290), 3% horse serum (Gibco 034-06050), 10% fresh ratserum, 1 nM T₃ (Sigma T-2752) and 40 mg/L dexamethasone (Sigma D4902) pH7.3, to a density of 2×10⁵ cells/ml. The cells were seeded intomicrotiter plates (Nunc, Denmark), 200 ml/well, and cultured for 3 daysat 37° C. and 8% CO₂.

Compound testing

After culturing, the cells were washed twice with stimulation buffer(Hanks Balanced Salt Solution (Gibco 041-04020) supplemented with 1% BSA(Sigma A-4503), 0.25% D-glucose (Sigma G-5250) and 25 mM HEPES (SigmaH-3375) pH 7.3) and preincubated for 1 hour at 37° C. The buffer wasexchanged with 90 ml stimulation buffer (37° C.). Ten ml test compoundsolution was added and the plates were incubated for 15 min at 37° C.and 5% CO₂. The medium was decanted and analyzed for GH content in anrGH SPA test system.

All compounds were tested in doses ranging from 10 pM to 100 mM. Adose-response relation was constructed using the Hill equation (Fig P,Biosoft). The efficacy (maximal GH released, E_(max)) was expressed in %of the E_(max) of GHRP-6. The potency (EC₅₀) was determined as theconcentration inducing half maximal stimulation of the GH release.

Compounds of formula I may be evaluated for their metabolic stability.

Compounds were dissolved at a concentration of 1 mg/ml in water. 25 mlof this solution is added to 175 ml of the respective enzyme-solution(resulting in an enzyme:substrate ratio (w/w) of approximately 1:5). Thesolution is left at 37° C. overnight. 10 ml of the various degradationsolutions is analyzed against a corresponding zero-sample using flowinjection electrospray mass spectrometry (ESMS) with selected ionmonitoring of the molecular ion. If the signal has decreased more than20% compared to the zero-sample, the remainder of the solution isanalyzed by HPLC and mass spectrometry in order to identify the extentand site(s) of degradation precisely.

Several standard peptides (ACTH 4-10, Angiotensin 1-14 and Glucagon)have been included in the stability tests in order to verify the abilityof the various solutions to degrade peptides.

Standard peptides (angiotensin 1-14, ACTH 4-10 and glucagon) werepurchased from Sigma, Mo., USA)

Enzymes (trypsin, chymotrypsin, elastase aminopeptidase M andcarboxypeptidase Y and B) were all purchased from Boehringer MannheimGmbH (Mannheim, Germany)

Pancreatic enzyme mix: trypsin, chymotrypsin and elastase in 100 mMammoniumbicarbonate pH 8.0 (all concentrations 0.025 mg/mI).

Carboxypeptidase mix: carboxypeptidase Y and B in 50 mM ammoniumacetatepH 4.5 (all concentrations 0.025 mg/ml).

Aminopeptidase M solution: aminopeptidase M (0.025 mg/ml) in 100 mMammoniumbicarbonate pH 8.0

Mass spectrometric analysis was performed using two different massspectrometers. A Sciex API III triple quadrupole LC-MS instrument (Sciexinstruments, Thornhill, Ontario) equipped with an electrosprayion-source and a Bio-Ion 20 time-of-flight Plasma Desorption instrument(Bio-Ion Nordic AB, Uppsala, Sweden).

Quantification of the compounds (before and after degradation) was doneon the API III instrument using single ion monitoring of the molecularion in question with flow injection of the analyte. The liquid flow(MeOH:water 1:1) of 100 ml/min was controlled by an ABI 140B HPLC unit(Perkin-Elmer Applied Biosystems Divisions, Foster City, Calif.). Theinstrument parameters were set to standard operation conditions, and SIMmonitoring was performed using the most intense molecular ion (in mostcases this corresponded to the doubly charged molecular ion).

Identification of degradation products furthermore involved the use ofplasma desorption mass pectrometry (POMS) with sample application onnitrocellulose coated targets and standard instrumental settings. Theaccuracy of the hereby determined masses is generally better than 0.1%.

Separation and isolation of degradation products was done using aHY-TACH C-18 reverse phase 4.6×105 mm HPLC column (Hewlett-PackardCompany, Palo Alto, Calif.) with a standard acetonitril: TFA separationgradient. The HPLC system used was HP1090M (Hewlett-Packard Company,Palo Alto, Calif.).

    ______________________________________    Peptide               Carboxy-    derivative MW/SIM ion peptidase    Standards  (amu)      mix        Pan. enzyme mix    ______________________________________    ACTH 4-10  1124.5/562.8                          +          -    Glucagon    3483/871.8                          -          -    Insulin (B23-               859.1/430.6    29)    Angiotensin               1760.1/881.0                          -          -    1-14    GHRP-2     817.4/409.6                          -          -    GHRP-6     872.6/437.4                          -          -    ______________________________________     +: Stable (less than 20% decrease in SIM signal after 24 h in degradation     solution)     -: Unstable (more than 20% decrease in SIM signal after 24 h in     degradation solution)

Any novel feature or combination of features described herein isconsidered essential to this invention.

EXAMPLES

The process for preparing compounds of formula I and preparationscontaining them is further illustrated in the following examples, whichhowever, are not to be construed as limiting.

The structures of the compounds are confirmed by either elementalanalysis (MA) nuclear magnetic resonance-(NMR) or mass spectrometry(MS). NMR shifts (d) are given in parts per million (ppm) and onlyselected peaks are given mp is melting point and is given in ° C. Columnchromatography was carried out using the technique described by W. C.Still et al, J. Org. Chem. 1978, 43, 2923-2925 on Merck silica gel 60(Art 9385). Compounds used as starting materials are either knowncompounds or compounds which can readily be prepared by methods knownper se.

Abbrevations:

TLC: thin layer chromatography

DMSO: dimethylsulfoxide

min: minutes

h: hours

HPLC-Analysis:

Method A1.

The RP-analysis was performed using UV detections at 214, 254, 276, and301 nm on a 218TP54 4.6 mm×250 mm 5 mm C-18 silica column (TheSeperations Group, Hesperia), which was eluted at 1 mL/min at 42° C. Thecolumn was equilibrated with 5% acetonitrile in a buffer consisting of0.1M ammonium sulfate, which was adjusted to pH 2.5 with 4M sulfuricacid. after injection the sample was eluted by a gradient of 5% to 60%acetonitrile in the same buffer during 50 min.

Example 1

(2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionicacid N-methyl-N-phenethylamide ##STR91##

N-Methyl-N-((1R)-1-(N-methyl-N-phenethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamicacid tert-butylester ##STR92##(2R)-2-(N-tert-Butoxycarbonyl-N-methylamino)-3-(2-naphthyl)propionicacid (1.40 g, 4.3 mmol) was dissolved in N,N-dimethylformamide (5 ml)and dichloromethane (5 mL). Hydroxy-7-azabenzotriazole (0.59 g, 4.3mmol) was added as a solid. The solution was cooled to 0° C.N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.99 g,5.2 mmol) was added. The solution was stirred for 20 min at 0° C.N-Methyl-N-phenethylamine (0.86 ml, 6.0 mmol) was added. The solutionwas stirred for 16 h, while it was warming up to room temperature. Itwas diluted with water (300 ml) and ethyl acetate (150 ml). 10% sodiumhydrogen sulfate solution (80 ml) was added. The phases were seperated.The aqueous phase was extracted with ethyl acetate (4×50 ml). Thecombined organic layers were washed with saturated sodium hydrogencarbonate solution (200 ml) and dried over magensium sulfate. Thesolvent was removed in vacuo. The crude product was purified by flashchromatography on silica (90 g), using ethyl acetate/heptane 1:1 aseluent to give 1.89 g ofN-methyl-N-((1R)-1-(N-methyl-N-phenethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamicacid tert-butylester.

¹ H-NMR (CDCl₃): d 1.01, 1.09, 1.25, and 1.30 (all s, together 9 H);2.60-3.85 (m, 12 H); 4.75, 5.03, 5.31, and 5.37 (all dd, together 1 H);7.00-7.85 (m, 12 H).

(2R)-2-(Methylamino)-3-(2-naphthyl)propionic acidN-methyl-N-phenethylamide ##STR93##N-Methyl-N-((1R)-1-(N-methyl-N-phenethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamicacid tert-butylester (1.84 g, 4.12 mmol) was dissolved indichloromethane (6 ml). The solution was cooled to 0° C. Trifluoroaceticacid (6 ml) was added. The solution was stirred for 10 min at 0° C. Thesolvent was removed in vacuo at 20° C. The residue was dissolved indichloromethane (100 ml) and the solvent was removed in vacuo. Thislatter procedure was repeated two times. The crude product was purifiedby flash chromatography on silica (70 g), usingdichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, togive 350 mg of (2R)-2-(methylamino)-3-(2-naphthyl)propionic acidN-methyl-N-phenethylamide.

¹ H-NMR (CDCl₃): d 1.72 (br, 1 H); 2.12, 2.30, 2.44, and 2.87 (all s,together 6 H); 2.58, 2.76, 2.91, 2.98, 3.09, 3.25, 3.50, 3.61, and 3.73(all m, together 7 H); 6.90-7.85 (m, 12 H).

(3E)-1,1-Dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-phenethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enylcarbamicacid tert-butylester ##STR94##(2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-3-enoic acid (303 mg, 1.04mmol) was dissolved in N,N-dimethylformamide (2 ml) and dichloromethane(2 ml). Hydroxy-7-azabenzotriazole (170 mg, 1.25 mmol) was added as asolid. The solution was cooled to 0° C.N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (299 mg,1.56 mmol) was added. The solution was stirred for 10 min at 0° C.(2R)-2-(Methylamino)-3-(2-naphthyl)propionic acidN-methyl-N-phenethylamide (360 mg, 1.04 mmol) was dissolved indichloromethane (2 ml) and added to the reaction mixture.Ethyldiisopropylamine (0.18 ml, 1.04 mmol) was added. The reactionmixture was stirred for 16 h, while it was warming to room temperature.The solution was diluted with water (200 ml) and ethyl acetate (150 ml).10% aqueous sodium hydrogen sulfate solution (50 ml) was added. Thephases were seperated, and the aqueous phase was extracted with ethylacetate (4×50 ml). The combined organic layers were washed withsaturated sodium hydrogen carbonate solution (200 ml) and dried overmagensium sulfate. The solvent was removed in vacuo. The crude productwas purified by flash chromatography on silica (110 g), using ethylacetate/heptane 1:1 as eluent, to give 546 mg of(3E)-1,1-dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-phenethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enylcarbamicacid tert-butylester.

¹ H-NMR (CDCl₃): d 1.14, 1.17, 1.23, and 1.26 (all s, together 6 H);1.38 and 1.41 (both s, together 9H); 2.40-3.10, 3.30-3.60, and 3.92 (allm, together 8 H); 2.78, 2.89, and 3.03 (all s, together 6 H); 4.28 and4.40 (both br, together 1 H); 5.78 and 5.85 (both dd, together 1 H);6.15 and 6.23 (both d, together 1 H); 6.70 and 6.80 (both m, together 1H); 7.00-7.85 (m, 12 H).

(3E)-1,1-dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-phenethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enylcarbamicacid tert-butylester (528 mg, 0.85 mmol) was dissolved indichloromethane (2 ml). Trifluoroacetic acid (2 ml) was added. Thesolution was stirred at room temperature for 10 min. The solvent wasremoved in vacuo at 20° C. The residue was dissolved in dichloroemethane(50 ml), and the solvent was removed in vacuo. This latter procedure wasrepeated two times. The crude product was purified by flashchromatography on silcia, using dichloromethane/methanol/25% aqueousammonia (100:10:1) as eluent to give 320 mg of the title compound asfree base. 100 mg of this was dissolved in ethyl acetate (3 ml). 3Mhydrogen chloride in ethyl acetate (0.7 ml) was added. The solvent wasremoved in vacuo. The residue was purified by two HPLC-chromatographieson a 25 mm×250 mm 10 m C18 silica column at 40° C. with a gradient of 30to 43% acetonitrile in a 0.1M ammonium sulfate buffer, which wasadjusted to pH 2.5 with 4M sulfuric acid. The peptide containingfractions were collected, diluted with 3 volumes of water and applied toa Sep-Pak® C18 cartridge (Waters part. #: 51910) which was equilibratedwith 0.1% trifluoroacetic acid. The peptide was eluted from the Sep-Pak®cartridge with 70% acetonitrile in a 0.1% trifluoroacetic acid solutionin water. The product was liophilized to give 10 mg of the titlecompound as trifluoroacetate.

HPLC (A1): R_(t) 34.27 min.

NMR (CDCl₃, selected values, free base): d 1.04, 1.05, 1.1 1, and 1.12(all s, together 6 H); 5.78 and 5.87 (both dd, together 1 H); 6.14 and6.23 (both d, together 1 H); 6.78 and 6.87 (both dt, together 1 H).

MS: 472.1 M+H!⁺.

Example 2

(2R)-2-(N-((2E)-5-((2R)-2-hydroxypropylamino)-5-methylhex-2-enoyl)-N-methylamino)-N-methyl-3-(2-naphthyl)-N-phenethylpropionamide##STR95##

(2R)-2-(N-((2E)-5-((2R)-2-(tert-Butoxydimethylsilyloxy)propylamino)-5-methylhex-2-enoyl)-N-methylamino)-N-methyl-3-(2-naphthyl)-N-phenethylpropionamid##STR96##

(2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionicacid N-methyl-N-phenethylamide (179 mg, 0.38 mmol) was dissolved inmethanol (10 ml). Glacial acetic acid (0.30 ml, 5.30 mmol) and molsieves (3 Å, 5.0 g) were added successively.(2R)-2-(tert-Butyldimethylsilyloxy)propanal (500 mg, 2.66 mmol) wasdissolved in methanol (3 ml) and added to the reaction mixture. Sodiumcyanoborohydride (95 mg, 1.51 mmol) was added as a solid. The reactionmixture was stirred for 3 h at room temperature. Another portion ofsodium cyanoborohydride (95 mg, 1.51 mmol) was added. The reactionmixture was stirred 16 h at room temperature. The mol sieves wasfiltered off through a plug of celite, which was washed with methanol(30 ml). The solvent was removed in vacuo. The residue was dissolved inwater/1N sodium hydroxide solution (50 ml/50 ml). The solution wasextracted with diethyl ether (3×50 ml). The combined organic layers weredried over magnesium sulfate. The solvent was removed in vacuo. Thecrude product was purified by flash chromatography on silica (60 g)using ethyl acetate/heptane/triethylamine (10:10:1) as eluent to give160 mg of(2R)-2-(N-((2E)-5-((2R)-2-(tert-butoxydimethylsilyloxy)-propylamino)-5-methylhex-2-enoyl)-N-methylamino)-N-methyl-3-(2-naphthyl)-N-phenethylpropionamide.

¹ H-NMR (CDCl₃, selected values): d=5.80 and 5.86 (t and dd, together 1H); 6.14 and 6.23 (both d, together 1 H); 6.85 (m, 1 H).

(2R)-2-(N-((2E)-5-((2R)-2-(tert-Butoxydimethylsilyloxy)-propylamino)-5-methylhex-2-enoyl)-N-methylamino)-N-methyl-3-(2-naphthyl)-N-phenethylpropionamide(135 mg, 0.21 mmol) was dissolved in THF (2 ml). An 1.1M solution oftertabutylammonium fluoride (0.42 ml, 0.46 mmol) was added. The reactionmixture was stirred for 1 h at room temperature. The solution wasdiluted with ethyl acetate (50 ml). It was extracted with saturatedsodium hydrogen carbonate solution (3×20 ml). The combined organiclayers were dried over magnesium sulfate. The solvents were removed invacuo. The residue was purified on silica (20 g), usingdichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent togive 24 mg of the crude product. The residue was purified byHPLC-chromatography on a 25 mm×250 mm 10 m C18 silica column at 40° C.with a gradient of 30.0 to 43.5% acetonitrile in a 0.1M ammonium sulfatebuffer, which was adjusted to pH 2.5 with 4M sulfuric acid. The peptidecontaining fractions were collected, diluted with 3 volumes of water andapplied to a Sep-Pak® C18 cartridge (Waters part. #: 51910) which wasequilibrated with 0.1% trifluoroacetic acid. The peptide was eluted fromthe Sep-Pak® cartridge with 70% acetonitrile in a 0.1% trifluoroaceticacid solution in water. The product was liophilized to give 10.7 mg ofthe title compound as trifluoroacetate.

HPLC:

R_(t) 35.13 (A1)

R_(t) 37.08 (B1)

MS:

530.8±0.5 (M+1)

Example 3

(2R)-2-((5R)-4-((2E)-5-Amino-5-methylhex-2-enoyl)-5-(2-naph-thyl)methyl-2-oxopiperazin-1-yl)-N-methyl-3-phenylpropionamide. ##STR97##((1R)-1-(((1R)-1-Methylcarbamoyl-2-phenylethylamino)methyl)-2-(2-naphthyl)ethyl)carbamicacid tert butyl ester. ##STR98##

D-Phenylalanine-N-methyl amide (1.50 g, 8.35 mmol) and(1R)-1-formyl-2-(2-naphthyl)ethylcarbamic acid tert-butyl ester (2.50 g,8.35 mmol) were dissolved in methanol (40 ml). Molsieves (3 Å, 30 g) andacetic acid (3 ml) were added and the mixture was cooled with ice andsodium cyanoborohydride (0.80 g, 12.5 mmol) was added. The mixture wasstirred overnight at room temperature. Water (30 ml) and saturatedaqueous sodium hydrogen carbonate (30 ml) were added and the mixture wasextracted with methylene chloride (3×40 ml). The combined organic phaseswere dried (magnesium sulfate) and the solvent was removed in vacuo. Theresidue was chromatographed on silica (3×30 cm) using ethylacetate/heptane (1:1) as eluent to afford 1.19 g of((1R)-1-(((1R)-1-methylcarbamoyl-2-phenylethylamino)methyl)-2-(2-naphthyl)ethyl)carbamicacid tert butyl ester

¹ H-NMR: (CDCl₃) d 1.37 (s, 9H); 2.32 (dd, 1H); 2.49-2.71 (m, 4H); 2.75(d, 3H); 3.21 (m, 2H); 3.94 (m, 1H); 4.32 (d, 1H); 7.12-7.81 (12 arom.H)

((1R)-1-((N-Chloroacetyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)amino)methyl)-2-(2-naphthyl)ethyl)carbamicacid tert butyl ester. ##STR99##((1R)-1-(((1R)-1-Methylcarbamoyl-2-phenylethylamino)methyl)-2-(2-naphthyl)ethyl)carbamicacid tert-butyl ester (1.00 g, 2.18 mmol) was dissolved in methylenechloride (20 ml).

Diisopropylethylamine (0.37 ml, 2.13 mmol) was added and the mixture wascooled with ice. Chloroacetic anhydride (0.37 g, 2.18 mmol) wasdissolved in methylene chloride (20 ml) and added dropwise. The mixturewas stirred overnight. Chloroacetic anhydride (0.18 g, 1.09 mmole wasadded) and the mixture was stirred 1 h. Water (20 ml) and methylenechloride (20 ml) were added and the organic phase was washed with anaqueous solution of sodium hydrogen sulphate (10%, 25 ml), a saturatedaqueous solution of sodium hydrogen carbonate (25 ml), and dried(magnesium sulfate) and the solvent was removed in vacuo. The residuewas chromatographed on silica (3×30 cm) using ethyl acetate/heptane(1:1) as eluent to afford 0.57 g of((1R)-1-((N-chloroacetyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)amino)methyl)-2-(2-naphthyl)ethyl)carbamicacid tert butyl ester

¹ H-NMR,: (CDCl₃) (selected peaks for major rotamer) d 1.38 (s, 9H);2.80 (d, 3H); 3.95 (m, 2H); 6.90-7.78 (12 arom. H)

ESMS: m/z 538

(R-2-(N-((2R)-2-Amino-3-(2-naphthyl)propyl)-N-chloroacetylamino)-N-methyl-3-phenylpropionamide.##STR100##((1R)-1-((N-Chloroacetyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)amino)methyl)-2-(2-naphthyl)ethyl)carbamicacid tert-butyl ester (0.56 g, 1.04 mmol) was dissolved in a mixture oftrifluoroacetic acid (4 ml) and methylene chloride (4 ml) and stirredfor 40 min. The solvent was removed in vacuo and methylene chloride wasadded and removed in vacuo (3×10 ml) to afford 0.69 g of(2R)-2-(N-((2R)-2-amino-3-(2-naphthyl)propyl)-N-chloroacetylamino)-N-methyl-3-phenylpropionamideas a trifluoroacetate.

¹ H-NMR: (CDCl₃)(selected peaks for major rotamer) d 2.67 (d, 3H); 3.85,3.95 (two d (AB-syst.), 2H); 4.55 (t, 1H).

ESMS: m/z: 438 (M+H)⁺

(2R)-N-Methyl-2-((5R)-5-((2-naphthyl)methyl)-2-oxopiperazin-1-yl)-3-phenylpropionamide.##STR101##(2R)-2-(N-((2R)-2-Amino-3-(2-naphthyl)propyl)-N-chloroacetyl-amino)-N-methyl-3-phenylpropionamide(0.69 g, 1.58 mmol) was dissolved in methanol (14 ml) and sodiumhydrogen carbonate (0.40 g, 4.73 mmol) and water (7 ml) were added. Themixture was stirred overnight at room temperature. The solvent wasremoved in vacuo and the residue was dissolved in a mixture of ethylacetate (30 ml) and saturated aqueous sodium hydrogen carbonate (20 ml).The mixture was extracted with ethyl acetate (4×20 ml). The combinedorganic phases were dried (magnesium sulfate) and the solvent wasremoved in vacuo. The residue was chromatographed on silica (2×20 cm)using methylene chloride/methanol/25% aqueous ammonia (100:10:1) toafford 0.19 g of(2R)-N-methyl-2-((5R)-5-((2-naphthyl)methyl)-2-oxopiperazin-1-yl)-3-phenylpropionamide

¹ H-NMR: (CDCl₃) d 2.74 (d, 3H); 2.78-3.05 (m, 5H); 3.22 (dd, 1H); 3.30(m, 1 H); 3.32, 3.55 (two d (AB-syst), 2H); 5.27 (dd, 1H); 6.34 (s(br),1H); 7.05-7.78 (12 arom. H).

ESMS: m/z 403 (M+H)⁺

((3E)-1,1-Dimethyl-5-((2R)-4-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-2-((2-naphthyl)methyl)-5-oxopiperazin-1-yl)-5-oxopent-3-enyl)carbamicacid tert-butyl ester. ##STR102##(2E)-5-Methyl-5-(tert-butyloxycarbonylamino)hex-2-enoic acid wasdissolved in methylene chloride (10 ml). 1-Hydroxy-7-azabenzotriazol (60mg, 0.46 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimidehydrochloride (100 mg, 0.51 mmol) were added and the mixture was stirredfor 15 min.(2R)-N-Methyl-2-((5R)-5-((2-naphthyl)methyl)-2-oxopiperazin-1-yl)-3-phenylpropionamide(185 mg, 0.46 mmol) and diisopropylethylamine (0.08 ml) were added andthe mixture was stirred overnight. Water (10 ml) and methylene chloride(10 ml) were added and the mixture was washed with an aqueous solutionof sodium hydrogen sulphate (10%, 20 ml), a saturated aqueous solutionof sodium hydrogen carbonate (20 ml), dried (magnesium sulfate) and thesolvent was removed in vacuo. The residue was chromatographed on silica(3×30 cm) using ethyl acetate/heptane (1:1) as eluent to afford 0.20 gof((3E)-1,1-dimethyl-5-((2R)-4-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-2-((2-naphthyl)methyl)-5-oxopiperazin-1-yl)-5-oxopent-3-enyl)carbamicacid tert-butyl ester.

¹ H-NMR: (CDCl₃)(selected peaks for major rotamer) d 1.21 (s, 6H); 1.38(s, 9H); 2.91 (d, 3H); 5.35 (dd, 1H); 5.42 (t, 1H);

((3E)-1,1-Dimethyl-5-((2R)-4-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-2-((2-naphthyl)methyl)-5-oxopiperazin-1-yl)-5-oxopent-3-enyl)carbamicacid tert-butyl ester (0.20 g, 0.32 mmol) was dissolved in methylenechloride (2 ml) and trifluoracetic acid (2 ml) and stirred for 7 min.Water (1 ml) and methylene chloride (10 ml) was added and pH wasadjusted to neutral with solid sodium hydrogen carbonate. The aqueousphase was extracted with methylene chloride (3×8 ml). The combinedorganic phases were dried (magnesium sulfate) and the solvent wasremoved in vacuo to afford 0.160 g of the title compound.

¹ H-NMR: (CDCl₃)(selected peaks for major rotamer) d 1.28 (s, 3H); 1.35(s, 3H); 2.75 (d, 3H); 4.05, 4.30 (AB, 2H); 5.05 (dd, 1H); 5.27 (dd,1H); 6.15 (d, 1H).

HPLC: r_(t) =28.8 min (A1)

Example 4

(2E)-5-Amino-5-methyl-N-methyl-N-((1R)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)hex-2-enamide##STR103## 3-Hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester:##STR104## At 0° C., ethyl chloroformate (1.101/2, 11.5 mmol) was givendropwise to a solution of 3-tert-butoxycarbonylamino-3-methylbutanoicacid (2.50 g, 11.5 mmol) and triethylamine (1.92 mL, 13.8 mmol) intetrahydrofuran (10 mL). The solution was stirred for 40 min at 0° C.The formed precipitate was filtered off and washed with tetrahydrofuran(20 mL). The liquid was immediately cooled to 0° C. A 2M solution oflithium boronhydride in tetrahydrofuran (14.4 mL, 28.8 mmol) was addeddropwise. The solution was stirred at 0° C. for 2 h, and then warmed toroom temperature over a period of 4 h. It was cooled to 0° C. Methanol(5 mL) was added carefully. 1N Hydrochloric acid (100 mL) was added. Thesolution was extracted with ethyl acetate (2×100 mL, 3×50 ml). Thecombined organic layers were washed with saturated sodium hydrogencarbonate solution (100 ml) and dried over magnesium sulfate. Thesolvent was removed in vacuo. The crude product was chromatographed onsilica (110 g) with ethyl acetate/heptane 1:2 to give 1.84 g of3-hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester.

¹ H-NMR (CDCl₃):₋₋ d 1.33 (s, 6 H); 1.44 (s, 9 H); 1.88 (t, 2 H); 1.94(br, 1 H); 3.75 (q, 2 H); 4.98 (br, 1 H).

3-(tert-Butoxycarbonylamino)-3-methylbutanal: ##STR105##Dimethylsufoxide (1.22 ml, 17.2 mmol) was added to a solution of oxalylchloride (1.1 ml, 12.9 mmol) at -78° C. in dichloromethane (15 ml). Themixture was stirred for 15 min at -78° C. A solution of3-hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester (1.75 g, 8.6mmol) in dichloromethane (10 ml) was added dropwise over a period of 15min. The solution was stirred at -78° C. for another 15 min.Triethylamine (6.0 ml, 43 mmol) was added. The solution was stirred at-78° C. for 5 min and then warmed to room temperature. The solution wasdiluted with dichloromethane (100 ml) and extracted with 1N hydrochloricacid (100 ml). The aqueous phase was extracted with dichloromethane (50ml). The combined organic layers were washed with saturated sodiumhydrogen carbonate solution (100 ml) and dried over magnesium sulfate.The solvent was removed in vacuo. The crude product was purified bycolumn chromatography on silica (140 g) with ethyl acetate/heptane (1:3)to give 1.10 g of 3-(tert-butoxycarbonylamino)-3-methylbutanal.

¹ H-NMR (CDCl₃):₋₋ d 1.39 (s, 6 H); 1.45 (s, 9 H); 2.85 (d, 2 H); 4.73(br. 1 H); 9.80 (t, 1 H).

Ethyl (2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoate: ##STR106##Triethylphoshonoacetate (1.96 ml, 9.8 mmol) was dissolved intetrahydrofuran (30 ml). Potassium tert-butoxide (1.10 g, 9.8 mmol) wasadded. The solution was stirred for 40 min at room temperature. Asolution of 3-(tert-butoxycarbonylamino)-3-methylbutanal (1.10 g, 5.5mmol) in Tetrahydrofuran (6 ml) was added. The solution was stirred atroom temperature for 75 min. It was diluted with ethyl acetate (100 ml)and 1N hydrochloric acid (100 ml). The phases were separated. Theaqueous phase was extracted with ethyl acetate (2×50 ml). The combinedorganic phases were washed with saturated sodium hydrogen carbonatesolution (60 ml) and dried over magnesium sulfate. The solvent wasremoved in vacuo. The crude product was purified by columnchromatography on silica (90 g) with ethyl acetate/hepatane (1:4) togive 1.27 g of ethyl(2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoate.

¹ H-NMR (CDCl₃):₋₋ d 1.30 (s, 6 H); 1.30 (t, 3 H); 1.46 (s, 9 H); 2.62(d, 2 H); 4.27 (q, 2 H); 4.42 (br, 1 H); 5.88 (d, 1 H); 6.94 (td, 1 H).

(2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoic acid: ##STR107##Ethyl (2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoate (1.233 g,4.54 mmol) was dissolved in dioxane (20 ml). Lithium hydroxide (0.120 g,5.00 mmol) was added as a solid. Water (10 ml) was added, until a clearsolution was reached. The solution was stirred 16 h at room temperature.The solution was diluted with water (70 ml) and was extracted withtert-butyl methyl ether (2×100 ml). The aqueous phase was acidified with1N sodium hydrogensulfate solution (pH=1) and was extracted withtert-butylmethylether (3×70 ml). The organic phases were combined anddried over magnesium sulfate. The solvent was removed in vacuo to give1.05 g of (2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid.The crude product was used for further syntheses.

¹ H-NMR (DMSO d₆):₋₋ d 1.15 (s, 6 H); 1.35 (s, 9 H); 2.53 (d, 2 H); 5.75(d, 1 H); 6.57 (br, 1 H); 6.75 (td, 1 H); 12.15 (s, 1 H).

N-(2-(2-Thienyl)ethyl)formamide: ##STR108## 2-(2-thienyl)ethylamine(15.0 g, 118 mmol) was dissolved in formic acid (120 ml) while coolingwith an water bath. The solution was cooled to 0° C. Acetic acidanhydride (45 ml) was added dropwise. The reaction mixture was stirredat room temperature for 3 h. It was cooled to 0° C., and water (45 ml)was added dropwise. The mixture was stirred for 16 h, while it waswarming up to room temperature. The solvent was removed in vacuo. Theresidue was dissolved in ethyl acetate (300 ml). The solution was washedwith water (2×150 ml) and saturated sodium hydrogen carbonate solution(200 ml). It was dried over magnesium sulfate. The solvent was removedin vacuo. The crude product was purified by flash chromatography onsilica (180 g), using ethyl acetate/heptane (2:1) as eluent to give14.30 g of N-(2-(2-thienyl)ethyl)formamide.

¹ H-NMR (CDCl₃):₋₋ d 3.07 (t, 2 H); 3.59 (q, 2 H); 5.90 (br, 1 H); 6.85(d, 1 H); 6.95 (dd, 1 H); 7.17 (d, 1 H); 8.12 (s, 1 H).

N-Methyl-N-(2-(2-thienyl)ethyl)amine: ##STR109##

At 7° C., a solution of N-(2-(2-thienyl)ethyl)formamide (9,98 g, 63.8mmol) in tetrahydrofuran (200 ml) was added to a suspension of sodiumborohydride (2.89 g, 76.5 mmol) in tetrahydrofuran (200 ml). The mixturewas stirred for 10 min. A solution of iodine (8.09 g, 31.9 mmol) intetrahydrofuran (200 ml) was added dropwise. The reaction mixture wasstirred for 30 min at 7° C. and 30 min at room temperature. It washeated to reflux for 16 h. The reaction mixture was cooled to 7° C.Methanol (500 ml) was added dropwise. The solvent was removed in vacuo.The residue was dissolved in 20% aqueous sodium hydroxide solution (500ml) and tert-butyl methyl ether (200 ml). The phases were separated. Theaqueous phase was extracted with tert-butyl methyl ether (2×200 ml). Thecombined organic layers were dried over magensium sulfate. The solventwas removed in vacuo. The crude product was purified by flashchromatography on silica (220 g), using dichloromethane/methanol/25%aqueous ammonia (100:10:1) as eluent to give 2.82 g ofN-methyl-N-(2-(2-thienyl)ethyl)amine.

¹ H-NMR (CDCl₃):₋₋ d 2.05 (s, 1 H); 2.46 (s, 3 H); 2.90 (t, 2 H); 3.04(t, 2 H); 6.84 (d, 1 H); 6.94 (dd, 1 H); 7.15 (d, 1 H).

N-Methyl-N-((1R)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamicacid tert-butyl ester: ##STR110##(2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid (4.52 g, 13.7 mmol) was dissolved in N,N-dimethylformamide (6 ml)and dichloromethane (6 ml). 1-Hydroxy-7-azabenzotriazole (1.86 g, 13.7mmol) was added as a solid. The solution was cooled to 0° C.N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.63 g,13.7 mmol) was added. The solution was stirred for 15 min at 0° C. Asolution of N-methyl-N-(2-(2-thienyl)ethyl)amine in dichloromethane (6ml) was added. Ethyldiisopropylamine (2.37 ml, 13.7 mmol) was added. Thereaction mixture was stirred for 16 h, while it was warming up to roomtemperature. It was diluted with ethyl acetate (200 ml). The mixture waswashed with 1N hydrochloric acid (150 ml) and saturated sodium hydrogencarbonate solution (150 ml). It was dried over magnesium sulfate. Thesolvent was removed in vacuo. The crude product was purified by flashchromatography on silcia (100 g), using ethyl acetate/heptane (1:2) aseluent to give 5.57 g ofN-methyl-N-((1R)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamicacid tert-butyl ester.

¹ H-NMR (CDCl₃, selected values):₋₋ d 4.84, 5.05, and 5.86 (dd, dd, andm, together 1 H); 6.60-7,90 (m, 10 H).

(2R)-N-Methyl-2-(methylamino)-3-(2-naphthyl)-N-(2-(2-thienyl)ethyl)propionamide:##STR111##N-Methyl-N-((1R)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamicacid tert-butyl ester (5.17 g, 11.4 mmol) was dissolved indichloromethane (12 ml). The solution was cooled to 0° C.Trifluoroacetic acid (12 ml) was added. The reaction mixture was stirredfor 15 min at 0° C. The solvent was removed in vacuo at 20° C. Theresidue was codistilled with dichloromethane (3×60 ml). The crudeproduct was purified by flash chromatography on silica (80 g), usingdichloromethane/methanol/25% aqueous (100:10:1) ammonia as eluent, togive 1.91 g of(2R)-N-methyl-2-(methylamino)-3-(2-naphthyl)-N-(2-(2-thienyl)ethyl)propionamide.

¹ H-NMR (CDCl₃):₋₋ d 2.18, 2.32, 2.46, and 2.89 (all s, together 6 H);2.50-3.60 (m, together 6 H); 3.65 and 3.75 (both dd, together 1 H); 6.58and 6.69 (both d, together 1 H); 6.87, 7.10, 7.35, 7.45, 7.76 (all m,together 8 H); 7.62 and 7.65 (both s, together 1 H).

(3E)-1,1-Dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enylcarbamicacid tert-butyl ester: ##STR112##

(2E)-5-tert-Butoxycarbonylamino-5-methylhex-2-enoic acid (380 mg, 1.56mmol) was dissolved in N,N-dimethylformamide (2 ml) and dichloromethane(2 ml). 1-Hydroxy-7-azabenzotriazole (299 mg, 1.56 mmol) was added as asolid. The solution was cooled to 0° C.N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (380 mg,1.56 mmol) was added. The solution was stirred for 15 min. at 0° C. Asolution of(2R)-N-methyl-2-(methylamino)-3-(2-naphthyl)-N-(2-(2-thienyl)ethyl)propionamide(500 mg, 1.42 mmol) in dichloromethane (2 ml) was added.Ethyldiisopropylamine (0.25 ml, 1.42 mmol) was added. The solution wasstirred for 16 h, while it was warming up to room temperature. It wasdiluted with ethyl acetate (70 ml) and washed with 1N hydrochloric acid(100 ml). The organic layer was washed with saturated sodium hydrogencarbonate solution (100 ml) and dried over magnesium sulfate. Thesolvent was removed in vacuo. The crude product was purified by flashchromatography on silica (150 g), using ethyl acetate/heptane (1:1) aseluent, to give 679 mg of(3E)-1,1-dimethyl4-(N-methyl-N-((1R)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enylcarbamicacid tert-butyl ester.

¹ H-NMR (CDCl₃, selected values):₋₋ d 1.14, 1.17, 1.21, and 1.24 (all s,together 6 H); 1.39 and 1.41 (both s, together 9 H); 2.82, 2.91, 3.03,and 3.06 (all s, together 6 H); 5.84 and 5.88 (both dd, together 1 H);6.15 and 6.26 (both d, together 1 H).

(3E)-1,1-Dimethyl4-(N-methyl-N-((1R)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enylcarbamicacid tert-butyl ester (640 mg, 1.11 mmol) was dissolved indichloromethane (3 ml). The solution was cooled to 0° C. Trifluoroaceticacid (3 ml) was added. The solution was stirred for 15 min at 0° C. Thesolvent was removed in vacuo without warming. The residue wascodistilled with dichloromethane (3×50 ml). The crude product waspurified by flash chromatography on silica (60 g), usingdichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, togive 416 mg of the title compound.

HPLC: R_(t) =33.48 min (A1).

B_(t) =35.13 min (B1).

MS: 478.2, M+H!⁺.

¹ H-NMR (CDCl₃, selected values):₋₋ d 1.04, 1.05, 1.11, and 1.11 (all s,together 6 H); 2.80, 2.90, 3.04 and 3.07 (all s, together 6 H); 5.83 and5.88 (both dd, together 1 H); 6.14 and 6.25 (both d, together 1 H).

For biological testing, the title compound was dissolved in 0.5M aceticacid and lyophilized.

Example 5

(2E)-5-Methyl-5-(methylamino)-N-methyl-N-((1R)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)hex-2-enamide##STR113## (2E)-5-(N-(tertButoxycarbonyl)-N-methylamino)-5-methylhex-2-enoic acid. ##STR114##(2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid (5.00 g;20.6 mmol) was dissolved in tetrahydrofuran (70 ml). Methyl iodide (10.3ml; 164 mmol) was added and the solution was cooled to 0° C. Sodiumhydride (60% in oil)(2.07 g; 61.6 mmol) was added in portions and thesolution was stirred at room temperature for four days. Ethyl acetate(70 ml) and water (60 ml) was added dropwise and the solvent was removedin vacuo. The crude product was dissolved in water (40 ml) and ether (40ml). The organic phase was washed with a saturated aqueous solution ofsodium hydrogencarbonate (30 ml). The aqueous phases were mixed and 5%aqueous citric acid was added to pH 3. The aqueous phase was extractedwith ethyl acetate (4×50 ml). The organic phase was washed with water(2×40 ml), an aqueous solution of sodium thiosulfate (5%; 40 ml), water(40 ml), dried over MgSO₄ and the solvent was removed in vacuo. Theresidue was dissolved in ethyl acetate (45 ml) and washed with anaqueous solution of sodium hydrogensulfate (10%; 3×30 ml), dried overMgSO₄ and concentrated in vacuo to give 4.00 g of(2E)-5-(N-(tert-butoxycarbonyl)-N-methylamino)-5-methylhex-2-enoic acid.

¹ H-NMR (CDCl₃): d 1.38 (s, 6H), 1.45 (s, 9H ); 2.80 (d, 2H); 2.85 (s,3H); 5.88 (d, 1H); 7.01 (q, 1H).

N-Methyl-N-((3E)-1,1-dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamicacid tert-butyl ester: ##STR115##(2E)-5-(N-(tert-Butoxycarbonyl)-N-methylamino)-5-methylhex-2-enoic acid(146 mg, 0.57 mmol) was dissolved in dichloromethane (2 ml) andN,N-dimethylformamide (2 ml). 1-Hydroxy-7-azabenzotriazole (72 mg, 0.57mmol) was added as a solid. The solution was cooled to 0° C.N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (109 mg,0.57 mmol) was added. The solution was stirred for 15 min at 0° C. Asolution of(2R)-N-Methyl-2-(methylamino)-3-(2-naphthyl)-N-(2-(2-thienyl)ethyl)propionamide(200 mg, 0.57 mmol) in dichloromethane (2 ml) was added.Ethyldiisopropylamine (0.1 ml, 0.57 mmol) was added. The reactionmixture was stirred for 16 h, while it was warming up to roomtemperature. It was diluted with ethyl acetate (50 ml) and washed with1N hydrochoric acid. The aqueous phase was extracted with ethyl acetate(2×20 ml). The combined organic layers were washed with saturated sodiumhydrogen carbonate solution (40 ml) and dried over magnesium sulfate.The solvent was removed in vacuo. The crude product was purified byflash chromatography on silica (80 g), using ethyl acetate/heptane aseluent, to give 270 mg ofN-methyl-N-((3E)-1,1-dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamicacid tert-butyl ester.

¹ H-NMR (CDCl₃, selected values): d 2.67, 2.76, 2.82, 2.90, 3.03, and3.05 (all s, together 9 H); 5.85 (m, 1 H); 6.10 and 6.22 (both d,together 1 H).

N-Methyl-N-((3E)-1,1-dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamicacid tert-butyl ester (221 mg, 0.37 mmol) was dissolved indichloromethane (2 ml). The solution was cooled to 0° C. Trifluoroaceticacid (2 ml) was added. The solution was stirred for 20 min at 0° C.Saturated sodium hydrogen carbonate solution (10 ml) was added. Themixture was adjusted to pH=9, with solid potassium carbonate. Themixture was diluted with water 820 ml). It was extracted with tert-butylmethyl ether (3×30 ml). The combined organic layers were dried overmagensium sulfate. The solvent was removed in vacuo. The crude productwas purified by flash chromatography on silica (30 g), usingdichloromethane/methanol/25% aqueous ammonia as eluent, to give 125 mgof the title compound.

¹ H-NMR (CDCl₃, selected values): d 1.00 and 1.08 (both s, together 6H); 2.23 and 2.30 (both s, together 3 H); 2.80, 2.89, 3.04, and 3.07(all s, together 6 H); 5.85 (m, 1 H); 6.13 and 6.25 (both d, together 1H).

HPLC: 33.27 min (A1)

35.28 min (B1).

MS: 492.0 M+H!.

For biological testing, it was transformed into the acetate byliophyillization from 0.5N acetic acid (25 ml).

Example 6

(2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-(N-methyl-N-(3-phenylpropyl)carbamoyl)-2-(2-naphthyl)ethyl)amide##STR116## N-(3-Phenylpropyl)formamide ##STR117## 3-Phenylproylamine (10ml, 70.0 mmol) was added at 0° C. dropwise to formic acid (80 ml).Acetic acid anhydride (30 ml) was added dropwise to the reactionmixture. After the addition the reaction mixture was warmed to roomtemperature. It was stirred for 2.5 h. It was cooled to 0° C. Water (30ml) was added dropwise. The reaction mixture was warmed to roomtemperature. The solvent was removed in vacuo. The residue was dissolvedin ethyl acetate (300 ml). The organic phase was washed with saturatedsodium chloride solution (2×150 ml) and with saturated sodium hydrogencarbonate solution (200 ml). It was dried over magnesium sulfate. Thesolvent was removed in vacuo to furnish 5.82 g ofN-(3-phenylpropyl)formamide, which was used without furtherpurification.

¹ H-NMR (CDCl₃): d 1.85 (m, 2 H); 2.65 (t, 2 H); 3.21 and 3.30 (both q,together 2 H); 5.85 (broad, 1 H); 7.10-7.50 (m, 5 H); 8.12 (s, 1 H).

N-Methyl-N-(3-phenylpropyl)amine ##STR118## N-(3-Phenylpropyl)formamide(5.70 g, 34.9 mmol) was dissolved in tetrahydrofuran (50 ml) and addeddropwise to a suspension of sodium borohydride (1.58 g, 41.91 mmol) intetrahydrofuran (100 ml), which was cooled to 7° C. A solution of iodine(4.42 g, 17.46 mmol) in tetrahydrofuran was added dropwise, while thetemperature was kept at 7° C. After the addition was finished, thereaction mixture was warmed to reflux for 16 h. The reaction mixture wascooled to 7° C., and methanol (250 ml) was added dropwise. The solventwas removed in vacuo. The residue was dissolved in 20% aqueous sodiumhydroxide solution (250 ml) and tert-butyl methyl ether (100 ml). Thephases were separated. The aqueous phase was extracted with tert-butylmethyl ether (2×100 ml). The combined organic layers were dried overmagnesium sulfate. The solvent was removed in vacuo. The crude productwas purified by flash chromatography on silica (400 g), usingdichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent togive 2.76 g of N-methyl-N-(3-phenylpropyl)amine.

¹ H-NMR (CDCl₃): d 1.85 (m, 2 H); 2.43 (s, 1 H); 2.50 (s, 3 H); 2.65 (m,4 H); 7.10-7.40 (m, 5 H).

N-Methyl-N-((1R)-1-(N-methyl-N-(3-phenylpropyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamicacid tert-butyl ester ##STR119## (2R)-²-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionic acid(2.21 g, 6.70 mmol) was dissolved in N,N-dimethylformamide (3 ml) anddichloromethane (6 ml). 1-Hydroxy-7-azabenzotriazole (0.91 g, 6.70 mmol)was added. The solution was cooled to 0° C.N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.28 g,6.70 mmol) was added. The reaction mixture was stirred for 15 min at 0°C. A solution of N-methyl-N-(3-phenylpropyl)amine (1.0 g, 6.7 mmol) indichloromethane (3 ml) was added. Ethyldiisopropylamine (1.2 ml, 6.7mmol) was added. The reaction mixture was stirred for 16 h, while it wasslowly warming up to room temperature. The solution was diluted withethyl acetate (100 ml). It was washed with 1N hydrochloric acid (100ml). The aqueous phase was extracted with ethyl acetate (100 ml). Thecombined organic layers were washed with saturated sodium hydrogencarbonate solution (100 ml) and dried over magnesium sulfate. Thesolvent was removed in vacuo. The crude product was purified by flashchromatography on silica (400 g), using ethyl acetate/heptane (1:3) aseluent to give 1.43 g ofN-methyl-N-((1R)-1-(N-methyl-N-(3-phenylpropyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamicacid tert-butyl ester.

¹ H-NMR (CDCl₃, selected values): d 1.25 (broad, 9 H); 1.79 (m, 2 H);2.88 (broad, 3 H); 5.05 and 5.45 (both m, together 1 H).

(2R)-N-Methyl-2-methylamino-3-(2-naphthyl)-N-(3-phenylpropyl)propionamide##STR120##

N-Methyl-N-((1R)-1-(N-methyl-N-(3-phenylpropyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamicacid tert-butyl ester (1.43 g, 3.10 mmol) was dissolved indichloromethane (5 ml). The solution was cooled to 0° C. Trifluoroaceticacid (5 ml) was added. The solution was stirred at 0° C. for 90 min.Dichloromethane (35 ml) and saturated sodium hydrogen carbonate solutionwere added. Solid sodium hydrogen carbonate was added until pH 7. Thephases were separated. The aqueous phase was extracted withdichloromethane (2×100 ml). The combined organic layers were dried overmagnesium sulfate. The solvent was removed in vacuo to give 0.91 g ofcrude(2R)-N-methyl-2-methylamino-3-(2-naphthyl)-N-(3-phenylpropyl)propionamide,which was used without further purification.

¹ H-NMR (CDCl₃, selected values): d 0.91-1.35 (m, 2 H); 2.35, 2.42,2.43, and 2.84 (all s, together 6 H); 3.64 and 3.92 (both dd, together 1H).

MS: 361.2 M+1!⁺.

((3E)-1,1-Dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-(3-phenylpropyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamicacid tert-butyl ester ##STR121##(2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoic acid (405 mg, 1.66mmol) was dissolved in N,N-dimethylformamide (4 ml) and dichloromethane(4 ml). 1-Hydroxy-7-azabenzotriazole (227 mg, 1.66 mmol) was added. Thesolution was cooled to 0° C.N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (319 mg,1.66 mmol) was added. The solution was stirred at 0° C. for 40 min. Asolution of(2R)-N-methyl-2-methylamino-3-(2-naphthyl)-N-(3-phenylpropyl)propionamide(600 mg, 1.66 mmol) in dichloromethane (4 ml) was added.Ethyldiisopropylamine (0.29 m., 1.66 mmol) was added. The solution wasstirred for 2 days, while it was slowly warming up to room temperature.The reaction mixture was diluted with ethyl acetate (100 ml) and washedwith 1N hydrochloric acid (100 ml). The aqueous phase was extracted withethyl acetate (2×50 ml). The combined organic layers were washed withsaturated sodium hydrogen carbonate solution (100 ml) and dried overmagnesium sulfate. The solvent was removed in vacuo. The crude productwas purified by flash chromatography on silica (180 g), using ethylacetate/hepaten (1:1) as eluent to give 706 mg of((3E)-1,1-dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-(3-phenylpropyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamicacid tert-butyl ester.

¹ H-NMR (CDCl₃, selected values): d 1.21, 1.24, 1.25, and 1.26 (all s,together 6 H); 1.41 (s, 9 H); 2.83, 2.83, 3.10, and 3.12 (all s,together 6 H); 5.88 and 5.97 (both dd, together 1 H); 6.25 (m, 1 H);6.80 (m, 1 H).

((3E)-1,1-Dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-(3-phenylpropyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamicacid tert-butyl ester was dissolved in dichloromethane (2 ml). Thesolution was cooled to 0° C. Trifluoroacetic acid (2 ml) was added. Thesolution was stirred at 0° C. for 55 min. Dichloromethane (13 ml) wasadded. A saturated aqueous solution of sodium hydrogen carbonate (16 ml)was added. Solid sodium hydrogen carbonate was added until pH 7. Thephases were separated. The aqueous phase was extracted withdichlormethane (2×50 ml). The combined organic layers were dried overmagnesium sulfate. The solvent was removed in vacuo. The crude productwas purified by flash chromatography on silica (80 g), usingdichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent togive 436 mg of the title compound.

¹ H-NMR (CDCl₃, selected values): d 1.10 and 1.11 (both s, together 6H); 2.85, 3.13, 3.15, and 3.50 (all s, together 6 H); 5.89 and 5.97(both dd, together 1 H); 6.23 and 6.24 (both d, together 1 H).

MS: 486.4; M+1!⁺

HPLC: 36.62 min (A1)

38.93 min (B1).

For biological testing, the title compound was transferred into itsacetate salt by lyophilization from 0.5M aqueous acetic acid (50 ml).

Example 7

(2R)-2-(N-(3-(1-Aminoethyl)benzoyl)-N-methylamino)-N-methyl-3-(2-naphthyl)-N-(2-(2-thienyl)ethyl)propionamide##STR122## Ammonium acetate (10.6 g, 138 mmol) was evaporated from dryethanol (100 ml), and re dissolved in dry methanol (100 ml) overmolecular sieves (3 Å, 3 g). 3-Acetylbenzonitrile (2.0 g, 13.8 mmol) wasadded. After 30 min at room temperature sodium cyanoborohydride (0.87 g,138 mmol) was added and eth reaction mixture was stirred for 18 h. Thereaction mixture was concentrated in vacuo and redissolved in water (100ml). Concentrated hydrochloric acid was added until pH 2, and theaqueous solution was extracted with ethyl acetate (2×100 ml). Theaqueous phase was adjusted to pH 11 with solid potassium hydroxide, andextrcted with dichloromethane (2×100 ml). The combined organic phaseswere dried (magnesium sulfae) and concentrated in vacuo. A concentratedsolution of hydrogen chloride in ethyl acetate (100 ml) was added, andthe solution was concentrated in vacuo. The residue was dissolved inethanol (25 ml) and sulfuric acid (9N, 25 ml) was added. After 16 h atroom temperature and 2 h at reflux temperature, the ethanol was removedby evaporation in vacuo and the residual aqueous mixture was adjusted topH >8, using solid potassium hydroxide. Di-tert.-butyldicarbonate (2.0g), dissolved in tetrahydrofuran (100 ml) was added at 0° C. After 18 hat room temperature, the reaction mixture was concentrated in vacuo andredissolved in water (100 ml). Solid citric acid was added until pH 5.The reaction mixture was extracted with dichloromethane (2×100 ml), andthe combined organic phases were dried (magnesium sulfae) andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (3×40 cm), using ethanol and dichloromethane (1:9) aseluent to give 1.1 g of 3-(1-(N-tert.-butoxycarbonyl)aminoethyl)benzoicacid.

(1-(3-(N-Methyl-N-((1R)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)phenyl)ethyl)carbamicacid tert-butyl ester ##STR123##3-(1-(t-Butyloxycarbonylamino)ethyl)benzoic acid (217 mg, 0.82 mmol) wasdissolved in dichloromethane (5 ml) and N,N-dimethylformamide (3 ml).1-Hydroxy-7-azabenzotriazole (111 mg, 0.82 mmol) was added. The solutionwas cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimidehydrochloride (157 mg, 0.82 mmol) was added. A solution of(2R)-N-Methyl-2-(methylamino)-3-(2-naphthyl)-N-(2-(2-thienyl)ethyl)propionamide(288 mg, 0.82 mmol) in dichloromethane (3 ml) was added.Ethyldiisopropylamine (0.14 ml, 0.82 mmol) was added. The reactionmixture was stirred for 16 h, while it was warming up to roomtemperature. It was diluted with ethyl acetate (80 ml) and washed with10% sodium hydrogen sulfate solution (50 ml). The aqueous phase wasextracted with ethyl acetate (2×40 ml). The combined organic layers werewashed with saturated sodium hydrogen carbonate solution (50 ml) anddried over magnesium sulfate. The solvent was removed in vacuo. Thecrude product was purified by flash chromatography on silcia (110 g),using ethyl acetate/heptane 1:1 as eluent, to give 479 mg of(1-(3-(N-methyl-N-((1R)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)phenyl)ethyl)carbamicacid tert-butyl ester.

¹ H-NMR (CDCl₃, selected peaks): d 1.43 (br, 9 H); 5.91 and 6.02 (bothdd, together 1 H).

MS: 600.0 M+H!⁺.

(1-(3-(N-Methyl-N-((1R)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)phenyl)ethyl)carbamicacid tert-butyl ester (479 mg, 0.80 mmol) was dissolved indichloromethane (2 ml) and cooled to 0° C. Trifluoroacetic acid (2 ml)was added. The reaction mixture was stirred for 35 min at 0° C. It wasdiluted with dichloromethane (8 ml). Saturated sodium hydrogen carbonatesolution (10 ml) was added carefully. Solid sodium hydrogen carbonatewas added until pH 7. Water was added, until a clear solution wasobtained. The phases were separated, and the aqueous phase was extractedwith dichloromethane (2×50 ml). The combined organic layers were driedover magnesium sulfate. The solvent was removed in vacuo. The crudeproduct was purified by flash chromatography on silica (70 g), usingdichloromethane/methanol/25% aqueous ammonia as eluent, to give 293 mgof the title compound.

¹ H-NMR (CDCl₃, selected peaks): d 1.15 and 1.27 (both d, together 3 H);2.87 (s, 3 H); 3.00 and 3.03 (both s, together 3 H); 5.90 and 6.00 (bothdd, together 1 H).

MS: 500.0 M+H!⁺.

HPLC: 34.30 (A1).

36.85 (B1).

For biological testing, the title compound was transferred into itsacetate salt, by lyophilization from 0.5N acetic acid (50 ml).

Example 8

(2E)-5-Amino-5-methylhex-2-enoic acidN-((1R)-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1((2-naphthyl)methyl)-2-oxoethyl)-N-methylamide ##STR124##N-((1R)-2-(1,2,3,4-Tetrahydroisoquinolin-2-yl)-1-((2-naphthyl)methyl)-2-oxoethyl)-N-methylcarbamicacid tert-butyl ester ##STR125##(2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid (7.41 g, 22.5 mmol) was dissolved in N,N-dimethylformamide (90 ml)and dichloromethane (110 ml). 1-Hydroxy-7-azabenzotriazole (3.06 g, 22.5mmol) was added. The mixture was cooled to 0° C.N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (4.32 g,22.5 mmol) was added. The solution was stirred for 15 min at 0° C.1,2,3,4-Tetrahydroqunoline (3.00 g, 22.5 mmol) and ethyldiisopropylamine(3.90 m., 22.5 mmol) were added. The reaction mixture was stirred for 16h, while it was warming up to room temperature. It was diluted withethyl acetate (80 ml) and extracted with 10% aquoeous sodium hydrogensulfate solution (250 ml). The aqueous phase was extracted with ethylacetate (3×60 ml). The combined organic layers were washed withsaturated sodium hydrogen carbonate solution (200 ml) and dried overmagnesium sulfate. The solvent was removed in vacuo. The crude productwas purified by flash chromatography on silica (130 g), using ethylacetate/heptane 1:2 as eluent to give 6.12 g ofN-((1R)-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1-((2-naphthyl)methyl)-2-oxoethyl)-N-methylcarbamicacid tert-butyl ester.

¹ H-NMR (CDCl₃, selected values): d 1.07, 1.22, and 1.28 (all s,together 9 H); 5.14 and 5.50 (m and q, together 1 H); 6.90-7.85 (m,together 11 H).

MS: 445.0 ( M+1!⁺).

mp: 121-126° C. (ethyl acetate/heptane).

C₂₈ H₃₂ N₂ O₃ (444.57)

calc. C 75.65 H 7.26 N 6.03

found C 75.92 H 7.53 N 6.07

(2R)-1-(1,2,3,4-Tetrahydroisoquinolin-2-yl)-2-(methylamino)-3-(2-naphthyl)-1-propanone##STR126##N-((1R)-2-(1,2,3,4-Tetrahydroisoquinolin-2-yl)-1-((2-naphthyl)methyl)-2-oxoethyl)-N-methylcarbamicacid tert-butyl ester (6.12 g, 13.8 mmol) was dissolved indichloromethane (40 ml). The solution was cooled to 0° C.Trifluoroacetic acid (40 ml) was added. The reaction mixture was stirredfor 90 min at 0° C. Dichloromethane (110 ml) and a saturated aqueoussolution of sodium hydrogen carbonate (150 ml) were added successively.Solid sodium hydrogen carbonate was added until pH 7 was obtained. Thephases were separated. The aqueous phase was extracted withdichloromethane (3×60 ml). The combined organic layers were dried overmagnesium sulfate. The solvent was removed in vacuo. The crude productwas purified by flash chromatography on silica (130 g), usingdichloromethane/methanol/25% aqueous ammonia 100:10:1 as eluent, to give2.20 g of(2R)-1-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2-(methylamino)-3-(2-naphthyl)-1-propanone.

¹ H-NMR (CDCl₃, selected values): d 2.34 and 2.35 (both s, together 3H); 4.36 and 4.85 (both d, together 1 H); 6.55-7.80 (m, together 11 H).

MS: 345.2 ( M+1!⁺).

((3E)-4-(N-((1R)-2-(1,2,3,4-Tetrahydroisoquinolin-2-yl)-1-((2-naphthyl)methyl)-2-oxoethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamicacid tert-butyl ester ##STR127##(2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoic acid (283 mg, 1.16mmol) was dissolved in N,N-dimethylformamide (5.5 ml) anddichloromethane (6.5 ml). 1-Hydroxy-7-azabenzotriazole (158 mg, 1.16mmol) was added. The mixture was cooled to 0° C.N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (223 mg,1.16 mmol) was added. The reaction mixture was stirred for 15 min at 0°C. A solution of(2R)-1-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2-(methylamino)-3-(2-naphthyl)-1-propanone(400 mg, 1.16 mmol) in dichloromethane (4 ml) and ethyldiisopropylamine(0.2 ml, 1.16 mmol) were added successively. The reaction mixture wasstirred for 16 h, while it was warming up to room temperature. I wasdiluted with ethyl acetate (60 ml) and washed with 10% aqueous sodiumhydrogen sulfate solution (60 ml). The aqueous phase was extracted withethyl acetate (3×50 ml). The combined organic layers were washed withsaturated sodium hydrogen carbonate solution (100 ml) and dried overmagnesium sulfate. The solvent was removed in vacuo. The crude productwas purified by flash chromatography on silica (80 g), using ethylacetate/heptane 1:1 as eluent to give 647 mg of((3E)-4-(N-((1R)-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)-1-((2-naphthyl)methyl)-2-oxoethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamicacid tert-butyl ester.

¹ H-NMR (CDCl₃, selected values): d 1.25 and 1.40 (m and s, together 15H); 2.97 and 3.09 (both s, together 3 H); 6.00 (t, 1 H); 6.07 and 6.23(both d, together 1 H); 6.65-7.85 (m, together 13 H).

((3E)-4-(N-((1R)-2-(1,2,3,4-Tetrahydroisoquinolin-2-yl)-1-((2-naphthyl)methyl)-2-oxoethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamicacid tert-butyl ester (647 mg, 1.14 mmol) was dissolved indichloromethane (3 ml). The solution was cooled to 0° C. Trifluoroaceticacid (3 ml) was added. The reaction mixture was stirred for 35 min at 0°C. Dichloromethane (12 ml) and a saturated aqueous solution of sodiumhydrogen carbonate (14 ml) were added. Solid sodium hydrogen carbonatewas added until pH 7 was obtained. The phases were separated. Theaqueous phase was extracted with dichloromethane (3×50 ml). The combinedorganic layers were dried over magnesium sulfate. The solvent wasremoved in vacuo. The crude product was purified by flash chromatographyon silica (80 g), using dichloromethane/methanol/25% aqueous ammonia100:10:1 as eluent, to give 234 mg of the title compound.

¹ H-NMR (CDCl₃, selected values): d 1.08 and 1.10 (both s, together 6H); 2.20 and 2.25 (both d, together 2 H); 2.96 and 3.08 (both s,together 3 H); 5.98 (m,1 H); 6.06 and 6.23 (both d, together 1 H);6.70-7.80 (m, 12 H).

MS: 470 ( M+1!⁺).

HPLC 33.48 min (A1).

35.43 min (B1).

For biological testing, the title compound was transferred into itsacetate salt by lyophilization with 0.5M acetic acid (50 ml).

Example 9

(2E)-5-Methyl-N-methyl-5-(methylamino)-N-((1R)-1-(N-methyl-N-phenethylcarbamoyl)-2-(2-naphthyl)ethyl)hex-2-enamide##STR128##N-Methyl-N-((3E)-4-(N-methyl-N-((1R)-1-(N-methyl-N-phenethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)-1,1-dimethylbut-3-enyl)carbamicacid tert-butyl ester ##STR129##(2E)-5-(N-(tert-Butoxycarbonyl)-N-methylamino)-5-methylhex-2-enoic acid(122 mg, 0.48 mmol) was dissolved in N,N-dimethylformamide (2 ml) anddichloromethane (2 ml). 1-Hydroxy-7-azabenzotriazole 0(65 mg, 0.48 mmol)was added. The solution was cooled to 0° C.N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (92 mg,0.48 mmol) was added. The reaction mixture was stirred for 15 min at 0°C. A solution of (2R)-2-(methylamino)-3-(2-naphthyl)propionic acidN-methyl-N-phenethylamide (165 mg, 0.48 mmol) in dichloromethane (2 ml)and ethyldiisopropylamine (0.083 ml, 0.48 mmol) were added successively.The solution was stirred for 16 h, while it was warming up to roomtemperature. It was diluted with ethyl acetate (50 ml) and washed with10% aqueous sodium hydrogen sulfate solution (50 ml). The aqueous phasewas extracted with ethyl acetate (2×10 ml). The combined organic layerswere washed with saturated aqueous sodium hydrogen carbonate solution(50 ml) and dried over magnesium sulfate. The solvent was removed invacuo. The crude product was purified by flash chromatography on silica(80 g), using ethyl acetate/heptane 1:1 as eluent to give 204 mg ofN-methyl-N-((3E)-4-(N-methyl-N-((1R)-1-(N-methyl-N-phenethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)-1,1-dimethylbut-3-enyl)carbamicacid tert-butyl ester.

¹ H-NMR (CDCl₃, selected values): d 0.90 and 0.92 (both s, together 6H); 5.80 and 5.86 (t and dd, together 1 H); 6.12 and 6.21 (both d,together 1 H); 6.80 (m, 1 H); 7.00-7.85 (m, 12 H).

N-Methyl-N-((3E)-4-(N-methyl-N-((1R)-1-(N-methyl-N-phenethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)-1,1-dimethylbut-3-enyl)carbamicacid tert-butyl ester (182 mg, 0.31 mmol) was dissolved indichloromethane (2 ml). The solution was cooled to 0° C. Trifluoroaceticacid (2 ml) was added. The reaction mixture was stirred at 0° C. for 20min. It was diluted with dichloromethane (50 ml). A saturated aqueoussolution of sodium hydrogen carbonate (10 ml) was added. Solid sodiumhydrogen carbonate was added until pH 7 was obtained. The phases wereseparated. The aqueous phase was extracted with dichloromethane (2×15ml). The combined organic layers were dried over magnesium sulfate. Thesolvent was removed in vacuo. The crude product was purified by flashchromatography on silica (45 g), using dichloromethane/methanol/25%aqueous ammonia 100:10:1 as eluent to give 80 mg of the title compound.

¹ H-NMR (CDCl₃, selected values): d 1.00 and 1.06 (both s, together 6H); 2.25 and 2.31 (both s, together 3 H); 2.76, 2.87, and 3.05 (all s,together 6 H); 5.77 and 5.85 (t and dd, together 1 H); 6.14 and 6.23(both d, together 1 H); 6.78 (m, 1 H); 7.00-7.90 (m, 12 H).

HPLC

34.30 min (A1).

36.28 min (B1).

MS: 486.0 ( M+1!⁺).

For biological testing, the title compound was transferred into itsacetate salt by lyophilization with 0.5M acetic acid (50 ml).

Example 10

(2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methyl-3-(2-naphthyl)propionamide##STR130## 2-(2-Hydroxyphenyl)-N-methylacetamide ##STR131##(2-Hydroxyphenyl)acetic acid (9.89 g, 63.7 mmol) and1-hydroxybenzotriazole hydrate (8.61 g, 63.7 mmol) were dissolved inN,N-dimethylformamide (50 ml) and dichloromethane (200 ml). The solutionwas cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimidehydrochloride (8.67 g, 63.7 mmol) was added. The reaction mixture wasstirred for 30 min at 0° C. A 8.0M solution of methyl amine (39 ml, 318mmol) was added. The reaction mixture was stirred for 16 h, while it wasslowly warming up to room temperature. It was diluted with ethyl acetate(600 ml) and washed with a 10% aqueous solution of sodium hydrogensulfate (2×300 ml). The combined aqueous phases were extracted withethyl acetate. The combined organic layers were washed with saturatedsodium hydrogen carbonate solution (300 ml) and dried over magnesiumsulfate. The solvent was removed in vacuo. The crude product waspurified by flash chromatography on silica (180 g), using ethylacetate/heptane (1:1) as eluent to give 4.90 g of2-(2-hydroxyphenyl)-N-methylacetamide.

mp: 105-106° C. (ethyl acetate/heptane).

¹ H-NMR (CDCl₃): d 2.82 (d, 3 H); 3.56 (s, 2 H); 6.20 (br, 1 H); 6.83(m, 1 H); 7.00 (m, 2 H); 7.18 (m, 1 H); 9.85 (s, 1 H).

Ethyl 2-(2-((N-methylcarbamoyl)methyl)phenoxy)acetate ##STR132##Potassium carbonate (2.81 g, 20.34 mmol) was given to a solution of2-(2-hydroxyphenyl)-N-methylacetamide (3.36 g, 20.34 mmol) in acetone(150 ml). Ethyl bromoacetate (2.13 ml, 19.32 mmol) and potassium iodide(166 mg, 1.02 mmol) were added successively. The reaction mixture washeated to reflux for 6 h. It was left at room temperature for 16 h. Thesolid was filtered off. The solvent was removed in vacuo. The crudeproduct was purified by flash chromatography on silica (80 g), usingethyl acetate/dichloromethane (1:1) as eluent, to give 5.00 g of ethyl2-(2-((N-methylcarbamoyl)methyl)phenoxy)acetate.

¹ H-NMR (CDCl₃): d 1.33 (t, 3 H); 2.74 (d, 3 H); 3.61 (s, 2 H); 4.30 (q,2 H); 4.70 (s, 2 H); 6.68 (br, 1 H); 6.76 (d, 1 H); 6.98 (t, 1 H); 7.24(t, 1 H); 7.32 (d, 1 H).

2-(2-(2-(Methylamino)ethyl)phenoxy)ethanol ##STR133## At 0° C. asolution of ethyl 2-(2-((N-methylcarbamoyl)methyl)phenoxy)acetate (5.00g, 19.9 mmol) in tetrahydrofuran (75 ml) was added dropwise to asuspension of sodium borohydride (2.26 g, 59.7 mmol) in tetrahydrofuran(75 ml). A solution of iodine (5.05 g, 19.9 mmol) in tetrahydrofuran(150 ml) was added dropwise. The solution was warmed to room temperatureand heated to reflux for 16 h. It was cooled to 0° C. Methanol (150 ml)was added dropwise. The solvent was removed in vacuo. The solid residuewas dissolved in 20% aqueous sodium hydroxide solution/tert-butyl methylether (150 ml/150 ml). The phases were separated. The aqueous phase wasextracted with tert-butyl methyl ether (3×150 ml). The combined organiclayers were dried over magnesium sulfate. The solvent was removed invacuo. The crude product was purified by flash chromatography on silica(80 g), using dichloromethane/methanol/10% aqueous ammonia (first:100:10:1, then 70:30:3) as eluent, to give 1.124 g of2-(2-(2-(Methylamino)ethyl)phenoxy)ethanol.

¹ H-NMR (CDCl₃): d 2.40 (s, 3 H); 2.82 (m, 2 H); 2.92 (m, 2 H); 3.05(br, 2 H); 3.94 (m, 2 H); 4.10 (m, 2 H); 6.87 (d, 1 H); 6.92 (t, 1 H);7.17 (m, 2 H).

N-((1R)-1-(N-(2-(2-(2-Hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamicacid tert-butyl ester ##STR134## At 0° C.N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (558 mg,2.91 mmol) was given to a solution of(2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid (959 g, 2.91 mmol) and 1-Hydroxy-7-azabenzotriazole (396 mg, 2.91mmol) in N,N-dimethylformamide (5 ml) and dichloromethane (5 ml). Thesolution was stirred for 20 min at 0° C. A solution of2-(2-(2-(Methylamino)ethyl)phenoxy)ethanol (608 mg, 2.91 mmol) indichloromethane (5 ml) and ethyldiisopropylamine (0.50 ml, 2.91 mmol)were added successively. The reaction mixture was stirred for 16 h,while it was warming up to room temperature. It was diluted with ethylacetate (150 ml) and washed with a 10% aqueous sodium hydrogen sulfatesolution (70 ml). The aqueous phase was extracted with ethyl acetate(2×30 ml). The combined organic layers were washed with saturated sodiumhydrogen carbonate soltuion (150 ml) and dried over magnesium sulfate.The solvent was removed in vacuo. The crude product was purified byflash chromatography on silica (110 g), using ethyl acetate/heptane(1:1) as eluent, to give 1.02 g ofN-((1R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamicacid tert-butyl ester.

¹ H-NMR (CDCl₃, selected values): d 1.00, 1.22, and 1.29 (all s,together 9 H); 4.88, 5.02, 5.20, and 5.39 (t, m, q, and t, together 2H).

MS: 507.2 ( M+H!⁺).

(2R)-N-(2-(2-(2-Hydroxyethoxy)phenyl)ethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide##STR135## At 0° C., trifluoroacetic acid (4 ml) was added to a solutionofN-((1R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamicacid tert-butyl ester (986 mg, 1.95 mmol) in dichloromethane (4 ml). Thesolution was stirred for 3 h at 0° C. Dichloromethane (50 ml) was added.A saturated solution of sodium hydrogen carbonate (30 ml) was added.Solid sodium hydrogen carbonate was added until pH 7 was obtained. Waterwas added until a clear solution was obtained. The phases wereseparated. The aqueous phase was extracted with dichloromethane (2×20ml). The combined organic layers were dried over magnesium sulfate. Thesolvent was removed in vacuo. The crude product was purified by flashchromatography on silica (80 g), using dichloromethane/methanol/25%aqueous ammonia (100:10:1) as eluent, to give 730 mg of(2R)-N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide.

¹ H-NMR (CDCl₃, selected values): d 2.25 and 2.30 (both s, together 3H); 2.50 and 2.89 (both s, together 3 H).

(3E)-4-(N-((1R)-1-(N-(2-(2-(2-Hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamicacid tert-butyl ester ##STR136## At 0° C.N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (125 mg,0.65 mmol) was added to a solution of(2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid (158 mg, 0.65mmol) and 1-hydroxy-7-azabenzotriazole (88 mg, 0.65 mmol) inN,N-dimethylformamide (3 ml) and dichloromethane (3 ml). The solutionwas stirred for 20 min at 0° C. A solution of(2R)-N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide(265 mg, 0.65 mmol) in dichlromethane (3 ml) and ethyldiisopropylamine(0.11 ml, 0.65 mmol) were added successively. The reaction mixture wasstirred for 16 h, while it was warming up to room temperature. It wasdiluted with ethyl acetate (200 ml) and washed with 10% aqueous sodiumhydrogen sulfate solution (100 ml). The aqueous phase was extracted withethyl acetate (2×50 ml). The combined organic layers were washed withsaturated aqueous sodium hydrogen carbonate solution (200 ml) and driedover magnesium sulfate. The solvent was removed in vacuo. The crudeproduct was purified by flash chromatography on silica (60 g), usingethyl acetate/heptane (first: 2:1 (500 ml), then: 3:1) as elutent, togive 378 mg of(3E)-4-(N-((1R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamicacid tert-butyl ester.

¹ H-NMR (CDCl₃, selected values): d 1.32 and 1.40 (both s, together 9H); 2.91 and 2.97 (both s, together 3 H); 3.02 and 3.05 (both s,together 3 H); 4.80 and 4.90 (both t, together 1 H); 5.69 and 5.87 (bothdd, together 1 H); 6.05 and 6.22 (both d, together 1 H).

(3E)-4-(N-((1R)-1-(N-(2-(2-(2-Hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamicacid tert-butyl ester (347 mg, 0.55 mmol) was dissolved indichloromethane (3 ml). The solution was cooled to 0° C. Trifluoroaceticacid (3 ml) was added. The reaction mixture was stirred at 0° C. for 30min. A saturated aqueous solution of sodium hydrogen carbonate (6 ml)was added dropwise. Solid sodium hydrogen carbonate was added until pH 7was obtained. The phases were separated. The aqueous phase was extractedwith dichloromethane (2×30 ml). The combined organic layers were driedover magnesium sulfate. The solvent was removed in vacuo. The crudeproduct was purified by flash chromatography on silica (15 g), usingdichloromethane/methanol/25% aqueous ammonia (first: 100:10:1, then:50:10:1) as eluent, to give 218 mg of the title compound.

¹ H-NMR (CDCl₃, selected values): d 1.04 and 1.12 (both s, together 6H); 2.93, 2.99, 3.02, and 3.07 (all s, together 6 H); 5.68 and 5.87(both dd, together 1 H); 6.05 and 6.25 (both d, together 1 H).

MS: 532.2 ( M+H!⁺).

HPLC:

32.75 min (A1).

33.82 min (B1).

For biological testing, the title compound was transferred into itsacetate salt by lyophilization with 0.5M acetic acid (50 ml).

Example 11

(2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-N-methyl-3-(2-naphthyl)-N-(2-(2-methylsulfonylaminophenyl)ethyl)propionamide##STR137## N-Methyl-2-(2-nitrophenyl)acetamide ##STR138##(2-Nitrophenyl)acetic acid (10.0 g, 55.21 mmol) was dissolved inN,N-dimethylformamide (15 ml) and dichloromethane (50 ml).1-Hydroxybenzotriazole hydrate (7.46 g, 55.21 mmol) was added. Thesolution was cooled to 0° C.N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (10.58 g,55.21 mmol) was added. The solution was stirred for 15 min at 0° C. A8.0M solution of methylamine in ethanol (10.3 ml, 82.81 mmol) andethyldiisopropylamine (9.55 ml, 55.21 mmol) were added successively. Thereaction mixture was stirred for 16 h, while it was warming up to roomtemperature. It was diluted with ethyl acetate (180 ml) and washed with10% aqueous sodium hydrogen sulfate solution (100 ml). The aqueous phasewas extracted with ethyl acetate (2×40 ml). The combined organic layerswere washed with saturated aqueous sodium hydrogen carbonate solution(200 ml) and dried over magnesium sulfate. The solvent was removed invacuo. The crude product was purified by flash chromatography on silica(200 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1)as eluent to give 8.01 g of N-methyl-2-(2-nitrophenyl)acetamide.

mp: 147° C. (dichloromethane/methanol/25% aqueous ammonia).

¹ H-NMR (CDCl₃) d 2.80 (d, 3 H); 3.82 (s, 2 H); 5.85 (br, 1 H);7.40-7.65 (m, 3 H); 8.04 (d, 1 H).

MS: 388.8 ( 2M+H!⁺), 195.2 ( M+H!⁺).

C₉ H₁₀ N₂ O₃ (194.2)

calc.: C 55.62 H 5.19 N 14.43

found: C 55.86 H 5.30 N 14.39

N-Methyl-N-(2-(2-nitrophenyl)ethyl)amine ##STR139## At 0° C., a solutionof N-methyl-2-(2-nitrophenyl)acetamide (7.00 g, 36.05 mmol) intetrahydrofuran (410 ml) was added dropwise to a suspension of sodiumborohydride (1.63 g, 43.25 mmol) in tetrahydrofuran (110 ml). A solutionof iodine (4.57 g, 18.02 mmol) in tetrahydrofuran (150 ml) was addeddropwise. The reaction mixture was warmed to reflux for 16 h. It wascooled to 0° C. Methanol (310 ml) was added dropwise. The solvent wasremoved in vacuo. The residue was dissolved in 20% aqueous sodiumhydoxide solution (300 ml) and tert-butyl methyl ether (200 ml). Thephases were separated. The aqueous phase was extracted with tert-butylmethyl ether (2×100 ml). The combined organic layers were dried overmagnesium sulfate. The solvent was removed in vacuo. The crude productwas purified by flash chromatography on silica (160 g), usingdichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, togive 1.28 g of N-methyl-N-(2-(2-nitrophenyl)ethyl)amine.

¹ H-NMR (CDCl₃) d 2.49 (s, 3 H); 2.50 (br, 1 H); 2.93 (t, 2 H); 3.12 (t,2 H); 7.39 (m, 2 H); 7.55 (m, 1 H); 7.91 (d, 1 H).

MS: 181.2 ( M+H!⁺).

N-Methyl-N-(2-(2-nitrophenyl)ethyl)carbamic acid tert-butyl ester##STR140## To a solution of N-methyl-N-(2-(2-nitrophenyl)ethyl)amine(529 mg, 2.9 mmol) in a 1N aqueous sodium hydroxide solution (2.9 ml,2.9 mmol) and tetrahydrofuran (3.0 ml), a solution of di-tert-butyldicarbonate(769 mg, 3.5 mmol) was added dropwise. The reaction mixturewas stirred for 16 h at room temperature. It was diluted with water (50ml) and ethyl acetate (50 ml). The phases were separated. The aqueousphase was extracted with ethyl acetate (3×50 ml). The combined organiclayers were washed with saturated aqeous sodium hydrogen carbonatesolution (50 ml) and dried over magnesium sulfate. The solvent wasremoved in vacuo. The crude product was purified by flash chromatographyon silica (50 g), using ethyl acetate/heptane (1:1) as eluent, to give924 mg of N-methyl-N-(2-(2-nitrophenyl)ethyl)carbamic acid tert-butylester.

¹ H-NMR (CDCl₃) d 1.35 and 1.44 (both br, together 9 H); 2.85 (br, 3 H);3.10 (br, 2 H); 3.56 (m, 2 H); 7.20-7.50 (br, 2 H); 7.55 (t, 1 H); 7.97(br, 1 H).

N-(2-(2-Aminophenyl)ethyl)-N-methylcarbamic acid tert-butyl ester##STR141## N-Methyl-N-(2-(2-nitrophenyl)ethyl)carbamic acid tert-butylester (924 mg, 3.3 mmol) was dissolved in ethanol (60 ml). 10% palladiumon carbon (200 mg) was added. The mixture was hydrogenated at roomtemperature at 1 atmosphere for 16 h. The catalyst was filtered offthrough a plug of celite. The solvent was removed in vacuo. The crudeproduct was purified by flash chromatography on silica (60 g), usingethyl acetate/heptane (1:2) as eluent, to give 723 mg ofN-(2-(2-aminophenyl)ethyl)-N-methylcarbamic acid tert-butyl ester.

¹ H-NMR (CDCl₃) d 1.47 (s, 9 H); 2.75 (t, 2 H); 2.90 (s, 3 H); 3.35 (br,2 H); 3.71 (br, 1 H); 4.23 (br, 1 H); 6.68 (m, 2 H); 7.00 (d, 1 H); 7.05(t, 1 H).

MS: 151.2 ( M+H!⁺).

N-(2-(2-(Methylsulfonylamino)phenyl)ethyl)-N-methylcarbamic acidtert-butyl ester ##STR142## A solution ofN-(2-(2-aminophenyl)ethyl)-N-methylcarbamic acid tert-butyl ester (723mg, 2.9 mmol) and triethylamine (0.48 ml, 3.5 mmol) in dichloromethane(10 ml) was cooled to -78° C. A solution of methanesulfonyl chloride(0.22 ml, 2.9 mmol) in dichloromethane (2 ml) was added dropwise. Thereaction mixture was stirred for 16 h, while it was warming up to roomtemperature. It was diluted with ethyl acetate (50 ml) and washed with10% aqueos sodium hydrogen sulfate solution (150 ml). The aqueous phasewas extracted with ethyl acetate (3×80 ml). The combined organic layerswere washed with saturated aqueous sodium hydrogen carbonate solution(150 ml) and dried over magnesium sulfate. The solvent was removed invacuo. The crude product was purified by flash chromatography on silica(60 g), using ethyl acetate/heptane (1:1) as eluent, to give 870 mg ofN-(2-(2-(methylsulfonylamino)phenyl)ethyl)-N-methylcarbamic acidtert-butyl ester.

¹ H-NMR (CDCl₃) d 1.50 (s, 9 H); 2.87 (m, 2 H); 2.91 (s, 3 H); 3.02 (s,3 H); 3.30 (br, 2 H); 7.05-7.30 (m, 3 H); 7.57 (br, 1 H); 8.65 (br, 1H).

N-(2-(2-(Methylamino)ethyl)phenyl)methanesulfonamide ##STR143## At 0°C., trifluoroacetic acid (6 ml) was added to a solution ofN-(2-(2-(methylsulfonylamino)phenyl)ethyl)-N-methylcarbamic acidtert-butyl ester (870 mg, 2.6 mmol) in dichloromethane (6 ml). Thereaction mixture was stirred for 50 min. Dichloromethane (24 ml) wasadded. A saturated aqueous solution of sodium hydrogen carbonate (34 ml)was added. Solid sodium hydrogen carbonate was added, until pH 7 wasobtained. The phases were separated. The aqueous phase was extractedwith dichloromethane (3×50 ml). The combined organic layers were driedover magnesium sulfate. The solvent was removed in vacuo. The crudeproduct was purified by flash crhomatography on silica (60 g), usingdichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent togive 308 mg of N-(2-(2-(methylamino)ethyl)phenyl)methanesulfonamide.

¹ H-NMR (CDCl₃) d 2.51 (s, 3 H); 2.84 (m, 2 H); 2.94 (m, 2 H); 3.00 (s,3 H); 5.70-6.70 (br, 1 H); 7.03 (m, 1 H); 7.12 (d, 1 H); 7.22 (t, 1 H);7.53 (d, 1 H).

N-((1R)-1-(N-(2-(2-(Methylsulfonylamino)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamicacid tert-butyl-ester ##STR144##(2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid (444 mg, 1.35 mmol) and successively 1-hydroxy-7-azabenzotriazole(1 84 mg, 1.35 mmol) were dissolved in N,N-dimethylformamide (5 ml) anddichloromethane (7 ml). The solution was cooled to 0° C.N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (259 mg,1.35 mmol) was added. The reaction mixture was stirred for 15 min at 0°C. A solution of N-(2-(2-(methylamino)ethyl)phenyl)methanesulfonamide(308 mg, 1.35 mmol) was added. Ethyldiisopropylamine (0.23 ml, 1.35mmol) was added. The reaction mixture was stirred for 16 h, while it waswarming up to room temperature. It was diluted with ethyl acetate andwashed with 10% aqueous sodium hydrogen sulfate solution (70 ml). Theaqueous phase was extracted with ethyl acetate (2×50 ml). The combinedorganic layers were washed with a saturated aqueous solution of sodiumhydrogen carbonate (150 ml) and dried over magnesium sulfate. Thesolvent was removed in vacuo. The crude product was purified by flashchromatography on silica (60 g), using ethyl acetateiheptane (1:1) aseluent, to give 245 mg ofN-((1R)-1-(N-(2-(2-(methylsulfonylamino)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamicacid tert-butyl-ester.

¹ H-NMR (CDCl₃, selected values) d 1.15, 1.20, and 1.35 (all s, together9 H); 4.83, 5.06, and 5.42 (all t, together 1 H); 8.07, 8.70, and 8.89(all br, together 1 H).

MS: 540.0 ( M+H!⁺).

(2R)-N-(2-(2-(Methylsulfonylamino)phenyl)ethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide##STR145## At 0° C., trifluoroacetic acid (1.5 ml) was added to asolution ofN-((1R)-1-(N-(2-(2-(methylsulfonylamino)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamicacid tert-butyl-ester (245 mg, 0.45 mmol) in dichloromethane (1.5 ml).The reaction mixture was stirred for 1.75 h at 0° C. Dichloromethane (5ml) and a saturated aqueous solution of sodium hydrogen carbonate (6 ml)were added successively. Solid soidum hydrogen carbonate was added untilpH 7 was obtained. The phases were separated. The aqueous phase wasextracted with dichloromethane (3×50 ml). The combined organic layerswere dried over magnesium sulfate. The solvent was removed in vacuo. Thecrude product was purified by flash chromatography on silica (30 g),using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent,to give 155 mg of(2R)-N-(2-(2-(methylsulfonylamino)phenyl)ethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide.

¹ H-NMR (CDCl₃, selected values) d 2.35 and 2.51 (both s, together 3 H);2.59 and 2.79 (both s, together 3 H); 2.94 and 3.07 (both s, together 3H); 3.80 and 3.95 (dd and t, together 1 H).

((3E)-4-(N-((1R)-1-(N-(2-(2-(Methylsulfonylamino)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamicacid tert-butyl ester ##STR146## A solution of(2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid (86 mg, 0.35mmol) and 1-hydroxy-7-azabenzotriazole (48 mg, 0.35 mmol) inN,N-dimethylformamide (1.5 ml) and dichloromethane (1.8 ml) was cooledto 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride(68 mg, 0.35 mmol) was added. The reaction mixture was stirred for 15min at 0° C. A solution of(2R)-N-(2-(2-(methylsulfonylamino)phenyl)ethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide(155 mg, 0.35 mmol) in dichloromethane (2 ml) and ethyldiisopropylamine(0.06 ml, 0.35 mmol) were added successively. The reaction mixture wasstirred for 16 h, while it was warming up to room temperature. It wasdiluted with ethyl acetate (50 ml) and washed with 10% aqueous sodiumhydrogen sulfate solution (50 ml). The aqueous phase was extracted withethyl acetate (3×20 ml). The combined organic layers were washed withsaturated aqueous sodium hydrogen carbonate solution (50 ml) and driedover magnesium sulfate. The solvent was removed in vacuo. The crudeproduct was purified by flash chromatography on silica (40 g), usingethyl acetate/heptane (2:1), as eluent, to give 174 mg of((3E)-4-(N-((1R)-1-(N-(2-(2-(methylsulfonylamino)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamicacid tert-butyl ester.

¹ H-NMR (CDCl3, selected values) d 5.58 and 5.88 (t and dd, together 1H); 6.16 and 6.28 (both d, together 1 H); 6.87 (m, 1 H).

At 0° C. trifluoroacetic acid (2 ml) was given to a solution of((3E)-4-(N-((1R)-1-(N-(2-(2-(methylsulfonylamino)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamicacid tert-butyl ester (168 mg, 0.25 mmol) in dichloromethane (2 ml). Thereaction mixture was stirred at 0° C. for 40 min. A saturated aqueoussolution of sodium hydrogen carbonate (6 ml) was added. Solid sodiumhydrogen carbonate was added until pH 7 was obtained. Water was added,until a clear solution was obtained. The phases were separated. Theaqueous phase wwas extracted with dichloromethane (3×20 ml). Thecombined organic layers were dried over magnesium sulfate. The solventwas removed in vacuo. The crude product was purified by flashchromatography on silica (15 g), using dichloromethanelmethanol/25%aqueous ammonia (100:10:1) as eluent to give 82 mg of the titlecompound.

¹ H-NMR (CDCl₃, selected values) d 1.08 and 1.15 (both s, together 1 H);2.93 and 2.95 (both s, together 3 H); 2.99 and 3.05 (both s, together 3H); 3.12 and 3.13 (both s, together 3 H); 5.57 and 5.88 (t and dd,together 1 H); 6.18 and 6.30 (both d, together 1 H).

MS: 565.0 ( M+H!⁺).

HPLC

32.08 min (A1).

32.53 min (B1).

For biological testing, the title compound was transferred into itsacetate salt by lyophilization with 0.5M acetic acid (40 ml).

Example 12

(2E)-5-Amino-N-((1R)-2-(biphenyl-4-yl)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)ethyl)-5-methyl-N-methylhex-2-enamide##STR147##(2R)-3-(Biphenyl-4-yl)-2-(N-tert-butyoxcarbony)-N-methylamino)-propionicacid ##STR148##(2R)-3-(Biphenyl-4-yl)-2-(tert-butyoxcarbonylamino)propionic acid (5.0g, 14.7 mmol) was dissolved in tetrahydrofurane (50 ml). Iodomethane(7.3 ml, 117.3 mmol) was added. The solution was cooled to 0° C. A 60%dispersion of sodium hydride in mineral oil (2.0 g, 44.0 mmol) was addedportionwise. The reaction mixture was stirred for 8 days at roomtemperature. Tetrahydrofurane (100 ml) was added. The reaction mixturewas cooled to 0° C. Methanol (50 ml) and successively water (20 ml) wereadded dropwise. The solvent was removed in vacuo. The resiude wasdissolved in tert-butyl methyl ether (30 ml) and a saturated aqueoussolution of sodium hydrogen carbonate (50 ml). The phases wereseparated. The aqueous phase was acidified to pH 3 with 5% aqueouscitric acid. It was extracted with ethyl acetate (2×100 ml). Theseextracts were washed with a 5% aqueous sodium thiosulfate solution(2×100 ml) and with brine (100 ml). They were dried over magnesiumsulfate. The solvent was removed in vacuo, to give 3.96 g of crude(2R)-3-(biphenyl-4-yl)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-propionicacid, which was used for the further steps without purification.

¹ H-NMR (DMSO d⁶): d 1.24 and 1.29 (both s, together 9 H); 2.64 and 2.66(both s, together 3 H); 2.95-3.40 (m, 2 H); 4.67 and 4.85 (both dd,together 1 H); 7.20-7.70 (m, 9 H); 12.83 (br, 1 H).

HPLC: 44.98 min (A1).

N-((1R)-2-(Biphenyl-4-yl)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)ethyl)-N-methylcarbamicacid tert-butyl ester ##STR149##(2R)-3-(Biphenyl-4-yl)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-propionicacid (753 mg, 2.12 mmol) and 1-hydroxy-7-azabenzotriazole (289 mg, 2.12mmol) were dissolved in N,N-dimethylformamide (6 ml) and dichloromethane(6 ml). The solution was cooled to 0° C.N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (406 mg,2.12 mmol) was added. The solution was stirred for 15 min at 0° C. Asolution of N-methyl-N-(2-(2-thienyl)ethyl)amine (300 mg, 2.12 mmol) indichloromethane (6 ml) was added. Ethyldiisopropylamine (0.37 ml, 2.12mmol) was added. The solution was stirred for 16 h, while it was warminup to room temperature. It was diluted with ethyl acetate (300 ml) andwashed with 10% aqueous sodium hydrogen sulfate solution (50 ml). Theaqueous phase was extracted with ethyl acetate (3×20 ml). The combinedorganic layers were washed with a saturated aqueous sodium hydrogencarbonate solution (60 ml) and dried over magnesium sulfate. The solventwas removed in vacuo. The crude product was purified by flashchromatography on silcia (60 g), using ethyl acetate/heptane (1:2) aseluent to give 1.03 g ofN-((1R)-2-(biphenyl-4-yl)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)ethyl)-N-methylcarbamicacid tert-butyl ester.

¹ H-NMR (CDCl₃, selected values): d 1.13, 1.21, 1.30, 1.36 (all s,together 9 H); 4.79, 4.97, and 5.31 (dd, dd, and m, together 1 H);6.70-7.60 (m, 12 H).

(2R)-3-(Biphenyl-4-yl)-N-methyl-2-(methylamino)-N-(2-(2-thienyl)ethyl)propionamide##STR150## At 0° C., trifluoroacetic acid (4 ml) was added to a solutionofN-((1R)-2-(biphenyl-4-yl)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)ethyl)-N-methylcarbamicacid tert-butyl ester (910 mg, 1.90 mmol) in dichloromethane (4 ml). Thereaction mixture was stirred for 3 h at 0° C. A saturated solution ofsodium hydrogen carbonate (8 ml) was added. Solid sodium hydrogencarbonate was added, until pH 7 was obtained. Water was added, until aclear solution was obtained. The phases were separated. The aqueousphase was extracted with dichloromethane (2×30 ml). The combined organiclayers were dried over magnesium sulfate. The solvent was removed invacuo. The crude produduct was purified by flash chromatogrphy on silica(60 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) aseluent, to give 674 mg of(2R)-3-(biphenyl-4-yl)-N-methyl-2-(methylamino)-N-(2-(2-thienyl)ethyl)propionamide.

¹ H-NMR (CDCl₃, selected values): d 2.20 and 2.30 (both s, together 6H); 2.59 and 2.90 (both s, together 3 H); 6.69, 6.78, 6.90, 7.12, and7.20-7.60 (all m, together 12 H).

(3E)-4-(N-((1R)-2-(Biphenyl-4-yl)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamicacid tert-butyl ester ##STR151## A solution of(2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid (202 mg, 0.83mmol) and 1-hydroxy-7-azabenzotriazole (113 mg, 0.83 mmol) inN,N-dimethyformamide (3 ml) and dichloromethane (3 ml) was cooled to 0°C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (159 mg,0.83 mmol) was added. The reaction mixture was stirred for 10 min at 0°C. A solution of(2R)-3-(biphenyl-4-yl)-N-methyl-2-(methylamino)-N-(2-(2-thienyl)ethyl)propionamide(314 mg, 0.83 mmol) in dichloromethane (3 ml) and ethyldiisopropylamine(0.14 ml, 0.83 mmol) were added successively. The reaction mixture wasstirred for 16 h, while it was warming up to room temperature. It wasdiluted with ethyl acetate (100 ml) and washed with a 10% aqueoussolution of sodium hydrogen sulfate (100 ml). The aqueous solution wasextracted with ethyl acetate (2×50 ml). The combined organic layers werewashed with a saturated solution of sodium hydrogen carbonate (100 ml)and dried over magnesium sulfate. The solvent was removed in vacuo. Thecrude product was purified on silica (80 g), using ethyl acetate/heptane(1:1 (500 ml), then 2:1) as eluent, to give 374 mg of(3E)-4-(N-((1R)-2-(biphenyl-4-yl)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamicacid tert-butyl ester.

¹ H-NMR (CDCl₃, selected values): d 1.25 and 1.26 (both s, together 6H); 1.39 and 1.40 (both s, together 9 H); 2.85, 2.89, 3.01, and 3.02(all s, together 6 H); 5.78 (m, 1 H); 6.20 and 6.26 (both d, together 1H); 6.67-6.90, 7.10, and 7.20-7.60 (all m, together 14 H).

At 0° C., trifluoroacetic acid (3 ml) was added to a solution of(3E)-4-(N-((1R)-2-(biphenyl-4-yl)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamicacid tert-butyl ester in dichloromethane (3 ml). The reaction mixturewas stirred for 30 min at 0° C. Dichloromethane (30 ml) was added. Asaturated aqueous solution of sodium hydrogen carbonate (10 ml) wasadded. Solid sodium hydrogen carbonate was added until pH 7. Water (30ml) was added. The phases were separated. The aqueous phase wasextracted with dichloromethane (3×15 ml). The combined organic layerswere dried over magnesium sulfate. The solvent was removed in vacuo. Thecrude product was purified by flash chromatography on silica (50 g),using dichloromethane/methanol/25% aqueous ammonia as eluent, to give152 mg of the title compound.

¹ H-NMR (CDCl₃, selected values): d 1.09 and 1.22 (both s, together 6H); 2.21 and 2.27 (both d, together 2 H); 2.85, 2.90, 3.07, and 3.08(all s, together 6 H); 5.78 (m, 1 H); 6.20 and 6.26 (both d, together 1H); 6.65-6.95, 7.09, and 7.20-7.60 (all m, together 13 H).

MS: 504.0 ( M+H!⁺).

HPLC

37.87 min (A1).

38.52 min (B1).

For biological testing, the title compound was transferred into itsacetate salt, by lyophilization with 0.5M acetic acid (40 ml).

Example 13

(2E)-N-((1R)-1-(N-(2-(2-(2-Hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methyl-5-methyl-5-(methylamino)hex-2-enamide##STR152##N-((3E)-4-(N-((1R)-1-(N-(2-(2-(2-Hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)-N-methylcarbamicacid tert-butyl ester ##STR153##(2E)-5-(N-(tert-Butoxycarbonyl)-N-methylamino)-5-methylhex-2-enoic acid(133 mg, 0.52 mmol) was dissolved in N,N-dimethylformamide (2 ml) anddichloromethane (2 ml). 1-Hydroxy-7-azabenzotriazole (71 mg, 0.52 mmol)was added. The solution was cooled to 0° C.N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (100 mg,0.52 mmol) was added. The solution was stirred for 10 min at 0° C. Asolution of(2R)-N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide(262 mg, 0.52 mmol) in dichloromethane (2 ml) and ethyldiisopropylamine(0.09 ml, 0.52 mmol) were added successively. The reaction mixture wasstirred for 16 h, while it was warming up to room temperature. It wasdiluted with ethyl acetate (30 ml) and washed with 10% sodium hydrogensulfate solution (20 ml). The aqueous phase was extracted with ethylacetate (2×20 ml). The combined organic layers were washed withsaturated sodium hydrogen carbonate solution (30 ml) and dried overmagnesium sulfate. The solvent was removed in vacuo. The crude productwas purified by flash chromatography on silica (100 g), using ethylacetate/heptane (2:1) as eluent, to give 261 mg ofN-((3E)-4-(N-((1R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)-N-methylcarbamicacid tert-butyl ester.

¹ H-NMR (CDCl₃, selected values): d 1.25, 1.26, 1.32, 1.33, 1.36, and1.43 (all s, together 15 H); 2.61, 2.75, 2.90, 2.91, 3.02, and 3.04 (alls, together 9 H); 4.85 and 5.02 (both t, together 1 H); 5.69 and 5.88(both dd, together 1 H); 6.02 and 6.22 (both d, together 1 H);6.60-7.85(m, 12).

At 0° C., trifluoroacetic acid (2 ml) was added to a solution ofN-((3E)-4-(N-((1R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)-N-methylcarbamicacid tert-butyl ester (236 mg, 0.37 mmol) in dichloromethane (2 ml). Thereaction mixture was stirred for 40 min at 0° C. A saturated solution ofsodium hydrogen carbonate (5 ml) was added. Solid sodium hydrogencarbonate was added, until pH 7 was obtained. Water (30 ml) anddichloromethane (30 ml) were added. The phases were separated. Theaqueous phase was extracted with dichloromethane (3×20 ml). The combinedorganic layers were dried over magnesium sulfate. The solvent wasremoved in vacuo. The crude product was purified by flash chromatographyon silica (60 g), using dichloromethane/methanol/25% aqueous ammonia(100:10:1) as eleuent to give 118 mg of the title comound.

¹ H-NMR (CDCl₃, selected values): d 1.02 and 1.10 (both s, together 6H); 2.27 and 2.32 (both s, together 3 H); 2.91, 2.98, 3.02, and 3.06(all s, together 6 H); 5.65 and 5.86 (both dd, together 1 H); 6.10 and6.25 (both d, together 1 H); 6.55-7.90 (m, 12 H).

MS: 546.0 ( M+H!⁺).

HPLC

33.47 min (A1).

34.25 min (B1).

For biological testing, the title compound was transferred into itsacetate salt, by lyophilization with 0.5M acetic acid (40 ml).

Example 14

3-Aminomethyl-N- (1R)-1-(N-{2-2-(2-hydroxyethoxy)phenyl!ethyl}-N-methylcarbamoyl)-2-(2-naphthyl)ethyl!benzamide##STR154## (1R)-1-(N-{2-2-(2-Hydroxyethoxy)phenyl!ethyl}-N-methylcarbamoyl)-2-(2-naphthyl)ethyl!carbamicacid tert-butyl ester ##STR155##(2R)-2-(tert-Butoxycarbonylamino)-3-(2-naphthyl)propionic acid (654 mg,2.07 mmol) was dissolved in N,N-dimethylformamide (4 ml) anddichloromethane (4 ml). 1-Hydroxy-7-azabenzotriazole (282 mg, 2.07 mmol)was added. The solution was cooled to 0° C.N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (397 mg,2.07 mmol) was added. The reaction mixture was stirred for 15 min at 0°C. A solution of 2-(2-(2-(methylamino)ethyl)phenoxy)ethanol (434 mg,2.07 mmol) in dichloromethane (4 ml) and ethyldiisopropylamine (0.36 ml,2.07 mmol) were added successively. The reaction mixture was stirred for16 h, while it was warming up to room temperature. It was diluted withethyl acetate (50 ml) and washed with a 10% aqueous solution of sodiumhydrogen sulfate (50 ml). The aqueous phase was extracted with ethylacetate (2×20 ml). The combined organic layers were washed with asaturated aqueous solution of sodium hydrogen carbonate (50 ml) anddried over magnesium sulfate. The solvent was removed in vacuo. Thecrude product was purified by flash chromatography on silica (70 g),using ethyl acetate/heptane 1:1 as eluent, to give 539 mg of(1R)-1-(N-{2-2-(2-hydroxyethoxy)phenyl!ethyl}-N-methylcarbamoyl)-2-(2-naphthyl)ethyl!carbamicacid tert-butyl ester.

¹ H-NMR (CDCl₃): d 1.39 and 1.41 (both s, together 9 H); 2.60 and 2.94(both s, together 3 H); 5.45 and 5.50 (both s, together 1 H).

(2R)-2-Amino-N-{2-2-(2-hydroxyethoxy)phenyl!ethyl}-N-methyl-3-(2-naphthyl)propionamide##STR156## A solution of (1R)-1-(N-{2-2-(2-hydroxyethoxy)phenyl!ethyl}-N-methylcarbamoyl)-2-(2-naphthyl)ethyl!carbamicacid tert-butyl ester (519 mg, 1.85 mmol) in dichloromethane (3 ml) wascooled to 0° C. Trifluoroacetic acid (3 mL) was added. The reactionmixture was stirred at 0° C. for 40 min. Dichloromethane (20 ml) wasadded. A saturated solution of sodium hydrogen carbonate (10 ml) wasadded dropwise. Solid sodium hydrogen carbonate was added, until pH 7was obtained. The phases were separated. The aqueous phase was extractedwith dichloromethane (3×20 ml). The combined organic layers were driedover magnesium sulfate. The solvent was removed in vacuo. The crudeproduct was purified by flash chromatography on silica (60 g), usingdichloromethane/methanol/25% aqueous ammonia, to give 377 mg of(2R)-2-amino-N-{2-2-(2-hydroxyethoxy)phenyl!ethyl}-N-methyl-3-(2-naphthyl)propionamide.

¹ H-NMR (CDCl₃): d 2.73 and 2.85 (both s, together 3 H); 3.50 (t, 1 H);7.60 and 7.65 (both s, together 1 H).

((3-((1R)-1-(N-(2-(2-(2-Hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethylcarbamoyl)phenyl)methyl)carbamicacid tert-butyl ester ##STR157##3-(tert-Butoxycarbonylaminomethyl)benzoic acid (113 mg, 0.45 mmol) and7-aza-1-hydroxybenzotriazole (61 mg, 0.45 mmol) were dissolved inN,N-dimethylformamide (1 ml) and dichloromethane (1 ml). The solutionwas cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimidehydrochloride (86 mg, 0.45 mmol) was added. The reaction mixture wasstirred for 15 min at 0° C. A solution of (2R)-2-amino-N-{2-2-(2-hydroxyethoxy)phenyl!ethyl}N-methyl-3-(2-naphthyl)propionamide (175mg, 0.45 mmol) and ethyldiisopropylamine (0.08 ml, 0.45 mmol) were addedsuccessively. The reaction mixture was stirred for 16 h, while it waswarming up to room temperature. It was diluted with ethyl acetate (50ml) and washed with a 10% aqueous solution of sodium hydrogen sulfate(50 ml). The aqueous phase was extracted with ethyl acetate (2×15 ml).The combined organic layers were washed with a saturated aqueoussolution of sodium hydrogen carbonate (50 ml) and dried over magnesiumsulfate. The solvent was removed in vacuo. The crude product waspurified by flash chromatography on silica (40 g), using ethylacetate/heptane 3:1 as eluent, to give 211 mg of((3-((1R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethylcarbamoyl)phenyl)methyl)carbamicacid tert-butyl ester.

¹ H-NMR (CDCl₃): d 1.45 (s, 9 H); 2.68 and 2.95 (both s, together 3 H);4.88 and 4.95 (both br, together 1 H); 5.46 (m, 1 H).

A solution of((3-((1R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethylcarbamoyl)phenyl)methyl)carbamicacid tert-butyl ester (193 mg, 0.31 mmol) in dichloromethane (2 ml) wascooled to 0° C. Trifluoroacetic acid (2 ml) was added. The reactionmixture was stirred for 20 min at 0° C. It was diluted withdichloromethane (10 ml). A saturated aqueous solution of sodium hydrogencarbonate (10 ml) was added. Solid sodium hydrogen carbonate was addeduntil pH 7 was obtained. The phases were separated. The aqueous phasewas extracted with dichloromethane (3×10 ml). The combined organiclayers were dried over magnesium sulfate. The solvent was removed invacuo. The crude product was purified by flash chromatography on silica(15 g), using dichloromethane/methanol/25% aqueous ammonia as eluent, togive 130 mg of the title compound.

¹ H-NMR (CDCl₃): d 2.75 and 3.04 (both s, together 3 H); 3.86 and 3.90(both s, together 2 H); 5.51 (m, 1 H).

HPLC:

32.63 min (A1);

39.5 min (B1).

MS: 525.8 ( M+H!⁺).

For biological testing, the title compound was transferred into itsacetate salt by lyophilization with 0.5M acetic acid (40 ml).

Example 15

(2E)-5-Amino-5-methylhex-2-enoic acidN-((1R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methylcarbomoyl)-2-(2-naphthyl)ethyl)amide##STR158## {(3E)-4-(1R)-(N-{2-Hydroxyethoxy)phenyl)!ethyl}-N-methylcarbamoyl)-2-(2-naphthyl)ethylcarbamoyl!-1,1-dimethylbut-3-enyl}carbamicacid tert-butyl ester ##STR159##(2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoic acid (95 mg, 0.39mmol) was dissolved in dichloromethane (1 ml) and N,N-dimethylformamide(1 ml). 1-Hydroxy-7-azabenzotriazole (55 mg, 0,39 mmol) was added. Thesolution was cooled to 0° C.N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (75 mg 0.39mmol) was added. The reaction mixture was stirred for 20 min at 0° C. Asolution of (2R)-2-amino-N-{2-2-(2-hydroxyethoxy)phenyl!ethyl}-N-methyl-3-(naphthyl)propionamide (155mg, 0.39 mmol) in dichloromethane (1 ml) and ethylduisopropylamine (0.07ml, 0.39 mmol) were added successively. The reaction mixture was stirredfor 16 h, while it was warming up to room temperature. It was dilutedwith ethyl acetate (30 ml) and washed with 10% aqueous sodium hydrogensulfate solution (30 ml). The aqueous phase was extracted with ethylacetate (2×20 ml). The combined organic layers were washed with asaturated aqueous solution of sodium hydrogen carbonate solution (30 ml)and dried over magnesium sulfate. The solvent was removed in vacuo. Thecrued product was purified by flash chromatography on silica (12 g),using ethyl acetate/heptane (2:1) as eluent to give 147 mg of {(3E)-4-(1R)-1-(N-{2-2-(2-hydroxyethoxy)phenyl!ethyl}-N-methylcarbamoyl)-2-(2-naphthyl)ethylcarbamoyl!-1,1-dimethylbut-3-enyl}carbamicacid tert-butyl ester.

¹ H-NMR (CDCl₃): d 1.42 (s, 9 H); 2.58 and 2.92 (both s, together 3 H);5.31 and 5.37 (both q, together 1 H); 5.80 and 5.87 (both d, together 1H).

{(3E)-4- (1R)-1-(N-{2-2-(2-Hydroxyethoxy)phenyl!ethyl}-N-4methylcarbamoyl)-naphthyl)ethylcarbamoyl!-1,1-dimethylbut-3-enyl}carbamicacid tert-butyl ester (129 mg, 0.21 mmol) was dissolved indichloromethane (2 ml). The solution was cooled to 0° C. Trifluoroaceticacid (2 ml) was added. The solution was stirred for 15 min at 0° C. Itwas diluted with dichloromethane (10 ml). A saturated aqueous solutionof sodium hydrogen carbonate (10 ml) was added. Solid sodium hydrogencarbonate was added, until pH 7 was obtained. The phases were separated.The aqueous phase was extracted with dichloromethane (3×10 ml). Thecombined organic layers were dried over magnesium sulfate. The solventwas removed in vacuo. The crude product was purified by flashchromatography on silica (25 g), using dichloromethane/methanol/25%aqueous ammonia as eluent, to give 71 mg of the title compound.

¹ H-NMR (CDCl₃): d 1.13 and 1.14 (both s, together 6 H); 2.24 ("t", 2H); 2.62 and 2.92 (both s, together 3 H); 5.32 and 5.39 (both q,together 1 H); 5.86 and 5.91 (both d, totether 1 H).

HPLC

31.92 min (A1).

36.57 min (B1).

MS: 518.0 ( M+H!⁺).

For biological testing, the title compound was transferred into itsacetate salt, by lyophilization with 0.5M acetic acid (40 ml).

Example 16

(2E)-5-Amino-5-methylhex-2-enoic acid N-((1R)-1-{N-2-(2-(benzenesulfonylamino)phenyl)ethyl!-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide##STR160## N- 2-(2-(Phenylsulfonylamino)phenyl)ethyl!-N-methylcarbamicacid tert-butyl ester ##STR161##N-(2-(2-Aminophenyl)ethyl)-N-methylcarbamic acid tert-butyl ester (555mg, 2.22 mmol) and triethylamine (0.40 ml, 2.66 mmol) were dissolved indichloromethane (12 ml) and cooled to -78° C. A solution ofbenzenesulfonyl chloride (0.28 ml, 2.22 mmol) in dichloromethane (3 ml)was added dropwise. The solution was stirred for 16 h, while it waswarming up to room temperature. It was diluted with ethyl acetate (40ml) and washed with 10% aqueous sodium hydrogen sulfate solution (20ml). The aqueous phase was extracted with ethyl acetate (2×15 ml). Thecombined organic layers were washed with saturated aqueous sodiumhydrogen carbonate solution (30 ml) and dried over magnesium sulfate.The solvent was removed in vacuo. The crude product was purified byflash chromatography on silica (30 g), using ethyl acetate/heptane 1:3as eluent, to give 557 mg of N-2-(2-(phenylsulfonylamino)phenyl)ethyl!-N-methylcarbamic acid tert-butylester.

¹ H-NMR (CDCl₃, selected values): d 1.55 (br, 9 H); 2.82 (br, 3 H); 8.80(br., 1 H).

N- 2-(2-(Methylamino)ethyl)phenyl!benzenesulfonamide ##STR162## N-2-(2-(Phenylsulfonylamino)phenyl)ethyl!-N-methylcarbamic acid tert-butylester (547 mg, 1.4 mmol) was dissolved in dichloromethane (5 ml). 3.1Nhydrogen chloride in ethyl acetate (3 ml, 9.3 mmol) was added. Thesolution was stirred at room temperature for 1 h. Another portion of3.1N hydrogen chloride in ethyl acetate (5 ml, 15.3 mmol) was added. Thesolution was stirred for another 3.5 h. The solvent was removed invacuo. The crude product was purified by flash chromatography on silcia(7 g), using dichloromethane/methanol/25% aqueous ammonia 50:10:1 aseluent, to give 521 mg of N-2-(2-(methylamino)ethyl)phenyl!benzenesulfonamide.

¹ H-NMR (CDCl₃, selected values): d 2.42 (m, 2 H), 2.50 (s, 3 H); 2.82(m, 2 H).

N-((1R)-1-{N-2-(2-(Phenylsulfonylamino)phenyl)ethyl!-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylcarbamicacid tert-butyl ester ##STR163##(2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid (517 mg, 1.57 mmol) and 1-hydroxy-7-azabenzotriazole (214 mg, 1.57mmol) were dissolved in dichloromethane (6 ml) and N,N-dimethylformamide(6 ml). The mixture was cooled to 0° C.N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (301 mg,1.57 mmol) was added. The reaction mixture was stirred for 15 min at 0°C. A solution of N- 2-(2-(methylamino)ethyl)phenyl!benzenesulfonamide(457 mg, 1.57 mmol) in dichloromethane (6 ml) and ethyldiisopropylamine(0.27 ml, 1.57 mmol) were added successively. The reaction mixture wasstirred for 16 h, while it was warming up to room temperature. It wasdiluted with ethyl acetate (100 ml) and washed with a 10% aqueous sodiumhydrogen sulfate solution (100 ml). The aqueous phase was extracted withethyl acetate (2×30 ml). The combined organic layers were washed with asaturated aqueous solution of sodium hydrogen carbonate and dried overmagnesium sulfate. The solvent was removed in vacuo. The crude productwas purified by flash chromatography on silica (25 g), using ethylacetate/heptane 1:1 as eluent, to give 785 mg of N-((1R)-1-{N-2-(2-(phenylsulfonylamino)phenyl)ethyl!-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylcarbamicacid tert-butyl ester.

¹ H-NMR (CDCl₃, selected values): d 4.80, 5.05, and 5.43 (dd, t, and t,together 1 H).

(2R)-N-2-(2-(Phenylsulfonylamino)phenyl)ethyl!-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide##STR164## At 0° C., trifluoroacetic acid (4 ml) was given to a solutionof N-((1R)-1-{N-2-(2-(phenylsulfonylamino)phenyl)ethyl!-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylcarbamicacid tert-butyl ester (647 mg, 1.08 mmol) in dichloromethane (4 ml). Thereaction mixture was stirred for 2.5 h at 0° C. It was diluted withdichloromethane (15 ml). A saturated aqueous solution of sodium hydrogencarbonate (15 ml) was added. Solid sodium hydrogen carbonate was addeduntil pH 7 was obtained. The phases were separated. The aqueous phasewas extracted with dichloromethane (2×15 ml). The combined organiclayers were dried over magnesium sulfate. The solvent was removed invacuo. The crude product was purified by flash chromatography on silica(20 g), using dichloromethane/methanol/25% aqueous ammonia 200:10:1 aseluent to give 434 mg of (2R)-N-2-(2-(phenylsulfonylamino)phenyl)ethyl!-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide.

¹ H-NMR (CDCl₃, selected values): d 2.37, 2.43, 2.52, and 2.75 (all s,together 6 H); 3.72 and 3.89 (dd and t, together 1 H).

{(3E)-4- N-((1R)-1-{N-2-(2-(Phenylsulfonylamino)phenyl)ethyl!-N-methylcarbamoyl}-2-2-naphthyl)ethyl)-N-methylcarbamoyl!-1,1-dimethylbut-3-enyl}carbamicacid tert-butyl ester ##STR165## At 0° C.,N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (138 mg,0.72 mmol) was added to a solution of(2E)-5-(tert.-butoxycarbonylamino)-5-methylhex-2-enoic acid (175 mg,0.72 mmol) and 1-hydroxy-7-azabenzotriazole (98 mg, 0.72 mmol) indichloromethane (3 ml) and N,N-dimethylformamide (3 ml). The reactionmixture was stirred for 20 min at 0° C. A solution of (2R)-N-2-(2-(phenylsulfonylamino)phenyl)ethyl!-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide(363 mg, 0.72 mmol) in dichloromethane (3ml) and ethyldiiso-propylamine(0.13 ml) were added successively. The reaction mixture was stirred for3 d, while it was warming up to room temperature. It was diluted withethyl acetate (60 ml) and washed with a 10% aqueous solution of sodiumhydrogen sulfate (60 ml). The aqueous phase was extracted with ethylacetate (2×30 ml). The combined organic layers were washed with asaturated aqueous solution of sodium hydrogen carbonate (60 ml) anddried over magnesium sulfate. The solvent was removed in vacuo. Thecrude product was purified by flash chromatography on silica (50 g),using ethyl acetate/heptane 1:1 as eluent, to give 363 mg of {(3E)-4-N-((1R)-1-{N-2-(2-(phenylsulfonylamino)phenyl)ethyl!-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylcarbamoyl!-1,1-dimethylbut-3-enyl}carbamicacid tert-butyl ester.

¹ H-NMR (CDCl₃, selected values): d 1.25 and 1.40 (both m, together 15H); 2.85 and 2.86 (both s, together 3 H); 3.12 and 3.18 (both s,together 3 H); 5.62 and 5.87 (t and dd, together 1 H); 6.20 and 6.31(both d, together 1 H).

A solution of {(3E)-4- N-((1R)-1-{N-2-(2-(phenylsulfonylamino)phenyl)ethyl!-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylcarbamoyl!-1,1-dimethylbut-3-enyl}carbamicacid tert-butyl ester (330 mg, 0.45 mmol) in dichloromethane (3 ml) wascooled to 0° C. Trifluoroacetic acid (3 ml) was added. The reactionmixture was stirred for 40 min at 0° C. It was diluted withdichloromethane (20 ml). A saturated aqueous solution of sodium hydrogencarbonate (6 ml) was added. Solid sodium hydrogen carbonate was addeduntil pH 7 was obtained. The phases were separated. The aqueous phasewas extracted with dichloromethane (3×20 ml). The combined organiclayers were dried over magnesium sulfate. The solvent was removed invacuo. The crude product was purified by flash chromatography on silica(20 g), using dichloromethane/methanol/25% aqueous ammonia 100:10:1 aseluent, to give 252 mg of the title compound.

¹ H-NMR (CDCl₃, selected values): d 1.09 and 1.12 (both s, together 6H); 2.84 and 2.86 (both s, together 3 H); 3.15 and 3.20 (both s,together 3 H); 5.65 and 5.87 (t and dd, together 1 H); 6.22 and 6.32(both d, together 1 H).

HPLC

37.87 min (A1).

40.23 min (B1).

MS: 627.2 ( M+H!⁺).

For biological testing, the title compound was transferred into itsacetate salt, by lyophilization with 0.5M acetic acid (40 ml).

Example 17

2-Amino-N-(2-(2-(N-((2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)ethyl)phenyl)acetamide##STR166## ({2-2-(N-(tert-Butoxycarbonyl)-N-methylamino)ethyl!phenylcarbamoyl}methyl)carbamicacid ((9-fluorenyl)methyl) ester ##STR167##2-(((9-Fluorenyl)methoxycarbonyl)amino)acetic acid (2.49 g, 2.79 mmol)was suspended in dichloromethane (40 ml). The suspension was cooled to0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (802mg, 4.19 mmol) was added. The reaction mixture was stirred for 30 min at0° C. A solution of N-(2-(2-aminophenyl)ethyl)-N-methylcarbamic acidtert-butyl ester (698 mg, 2.79 mmol) in dichloromethane (15 ml) wasadded. The reaction mixture was stirred for 16 h, while it was warmingup to room temperature. It was diluted with dichloromethane (100 ml) andwashed with brine (100 ml). The aqueous solution was extracted withdichloromethane (2×30 ml). The combined organic layers were dried overmagnesium sulfate. The solvent was removed in vacuo. The crude productwas purified by flash chromatography on silica (80 g), using ethylacetate/heptane (1:1) as eluent, to give 1.412 g of ({2-2-(N-(tert-butoxycarbonyl)-N-methylamino)ethyl!phenylcarbamoyl}methyl)carbamicacid ((9-fluorenyl)methyl) ester.

¹ H-NMR (CDCl₃, seleceted values): d 1.50 (br, 9 H); 2.80 (m, 2 H); 2.98(br, 3 H); 3.22 (m, 2 H); 4.25 (m, 3 H); 4.40 (m, 2 H); 6.32 (br, 1 H);9.20 (br, 1 H).

{ 2-(2-(Methylamino)ethyl)phenylcarbamoyl!methyl}carbamic acid9H-((fluoren-9-yl)methyl) ester ##STR168## ({2-2-(N-(tert-Butoxycarbonyl)-N-methylamino)ethyl!phenylcarbamoyl}methyl)carbamicacid ((9-fluorenyl)methyl) ester (1.342 g, 2.53 mmol) was dissolved in3.0M hydrogen chloride in ethyl acetate (10 ml). The reaction mixturewas stirred for 2 h at room temperature. Diethyl ether (40 ml) wasadded. The precipitation was filtered off and dried in vacuo to give 857mg of crude { 2-(2-(methylamino)ethyl)phenylcarbamoyl!methyl}carbamicacid 9H-((fluoren-9-yl)methyl) ester as hydrochloride, which was usedfor the next step without purification.

¹ H-NMR (DMSO-d₆, seleceted values): d 2.99 (br, 4 H); 9.05 (br, 2 H);9.68 (br, 1 H).

N-{(1R)-1- N-(2-{2-2-((Fluoren-9-ylmethoxycarbonyl)amino)acetylamino!phenyl}ethyl)-N-methylcarbamoyl!-2-(2-naphthyl)ethyl}-N-methylcarbamicacid tert-butyl ester ##STR169##(2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid (590 mg, 1.79 mmol) and 1-hydroxy-7-azabenzotriazole (243 mg, 1.79mmol) were dissolved in dichloromethane (12 ml) andN,N-dimethylformamide (6 ml). The solution was cooled to 0° C.N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (343 mg,1.79 mmol) was added. The solution was stirred for 25 min at 0° C. Thehydrochloride of {2-(2-(methylamino)ethyl)phenylcarbamoyl!methyl}carbamic acid9H-((fluoren-9-yl)methyl) ester (834 mg, 1.79 mmol) andethyldiisopropylamine (0.62 ml, 3.58 mmol) were added successively. Thereaction mixture was stirred for 16 h, while it was warming up to roomtemperature. It was diluted with ethyl acetate (30 ml) and washed with10% aqueous sodium hydrogen sulfate solution (30 ml). The aqueous phasewas extracted with ethyl acetate (3×30 ml). The combined organic layerswere washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml) and dried over magnesium sulfate. The solvent wasremoved in vacuo. The crude product was purified by flash chromatographyon silica (60 g), using ethyl acetate/heptane (1:1) as eluent, to give1.293 g of N-{(1R)-1- N-(2-{2-2-((fluoren-9-ylmethoxycarbonyl)amino)acetylamino!phenyl}ethyl)-N-methylcarbamoyl!-2-(2-naphthyl)ethyl}-N-methylcarbamicacid tert-butyl ester.

¹ H-NMR (CDCl₃, selected values): d (1.25 and 1.30, both br, together 9H); 2.85, 3.03 and 3.04 (all s, togetether 6 H); 5.08 and 5.45 (both t,together 1 H); 9.31 and 9.45 (both s, together 1 H).

(2-{2-N-Methyl-N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)amino!ethyl}phenylcarbamoyl)methyl!carbamicacid (fluoren-9-yl)methyl ester ##STR170## N-{(1R)-1- N-(2-{2-2-((Fluoren-9-ylmethoxycarbonyl)amino)acetylamino!phenyl}ethyl)-N-methylcarbamoyl!-2-(2-naphthyl)ethyl}-N-methylcarbamicacid tert-butyl ester (1.18 g, 1.59 mmol) was dissolved in 3.0M hydrogenchloride in ethyl acetate (8 ml). The reaction mixture was stirred for2.25 h at room temperature. The solvent was removed in vacuo. Theresidue was washed with diethyl ether (3×20 ml) and dried in vacuo togive 1.198 g of crude (2-{2-N-methyl-N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)amino!ethyl}phenylcarbamoyl)methyl!carbamicacid (fluoren-9-yl)methyl ester as hydrochloride, which was used for thenext step without purification.

¹ H-NMR (DMSO-d₆, seleceted values): d 4.41 and 4.67 (both m, together 1H).

(3E)-4-(N-((1R)-1-(N-(2-(2-((((9-Fluorenyl)methoxycarbonyl)amino)acetylamino)phenyl)ethyl)-N-methylcarbmoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamicacid tert-butyl ester ##STR171##(2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoic acid (200 mg, 0.82mmol) and 1-hydroxy-7-azabenzotriazole (112 mg, 0.82 mmol) weredissolved in dichloromethane (4 ml) and N,N-dimethylformamide (2 ml).The solution was cooled to 0° C.N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (157 mg,0.82 mmol) was added. The reaction mixture was stirred for 20 min at 0°C. The hydrochloride of crude (2-{2-N-methyl-N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)amino!ethyl}phenylcarbamoyl)methyl!carbamicacid (fluoren-9-yl)methyl ester (553 mg, 0.82 mmol) andethyldiisopropylamine (0.28 ml, 1.64 mmol) were added successively. Thereaction mixture was stirred for 16 h, while it was warming up to roomtemperature. It was diluted with ethyl acetate (50 ml) and washed with10% aqueous sodium hydrogen sulfate solution (50 ml). The aqueous phasewas extracted with ethyl acetate (2×20 ml). The combined organic layerswere washed with a saturated aqueous solution of sodium hdyrogencarbonate (50 ml) and dried over magnesium sulfate. The solvent wasremoved in vacuo. The crude product was purified by flash chromatographyon silca (40 g), using ethyl acetate/heptane (2:1) as eluent, to give265 mg of(3E)-4-(N-((1R)-1-(N-(2-(2-((((9H-9-fluorenyl)methoxycarbonyl)amino)acetylamino)phenyl)ethyl)-N-methylcarbmoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamicacid tert-butyl ester.

¹ H-NMR (CDCl₃, selected values): d 5.51 and 5.94 (t and dd, together 1H); 6.13 and 6.25 (both d, together 1 H); 6.25 (br, 1 H); 6.75 and 6.83(both m, together 1 H).

(3E)-4-(N-((1R)-1-(N-(2-(2-(2-Aminoacetylamino)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamicacid tert-butyl ester ##STR172## At room temperaturetris(2-aminoethyl)amine (2.99 ml, 19.8 mmol) was added to a solution of(3E)-4-(N-((1R)-1-(N-(2-(2-((((9-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamicacid tert-butyl ester (346 mg, 0.40 mmol) in dichloromethane (2.8 ml).The reaction mixture was stirred for 1.2 h at room temperature. It wasdiluted with dichloromethane (40 ml) and washed with brine (50 ml). Theaqueous phase was extracted wtih dichloromethane (3×20 ml). The combinedorganic layers were washed with buffer of sodium dihyrogen phosphate anddipotassium hydrogen phosphate (pH 6.4, 3×30 ml) and successively withbrine (20 ml). They were dried over magnesium sulfate. The solvent wasremoved in vacuo. The crude product was purified by flash chromatographyon silica (40 g), using dichloromethane/methanol/25% aqueous ammonia(100:10:1) as eluent, to give 185 mg of(3E)-4-(N-((1R)-1-(N-(2-(2-(2-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamicacid tert-butyl ester.

¹ H-NMR (CDCl₃, selected values): d 1.14, 1.15, 1.23, and 1.24 (all s,together 6 H); 1.39 and 1.40 (both s, together 9 H); 2.90, 2.94, 3.02,and 3.10 (all s, together 6 H); 5.64 and 5.90 (t and dd, together 1 H);6.12 and 6.26 (both d, together 1 H); 6.63 and 6.82 (both m, together 1H); 9.42 and 9.53 (both br, together 1 H).

(3E)-4-(N-((1R)-1-(N-(2-(2-(2-Aminoacetylamino)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamicacid tert-butyl ester (175 mg, 0.27 mmol) was dissolved indichloromethane (2 ml). The solution was cooled to 0° C. Trifluoroaceticacid (2 ml) was added. The reaction mixture was stirred for 25 min at 0°C. Dichloromethane (20 ml) and ethanol (20 ml) were added successively.The solvent was removed in vacuo without warming. The residue wasdissolved in dichlromethane (40 ml) and the solvent was removed invacuo. The last procedure was repeated. The crude product was purifiedby flash chromatography on silica (15 g), usingdichloromethane/methanol/25% aqueous ammonia /(first: 100:10:1, then:100:20:2) as eluent, to give 128 mg of the title compound.

¹ H-NMR (CDCl₃, selected values): d 1.03 and 1.12 (both s, together 6H); 2.92, 2,94, 3.01, and 3.12 (all s, together 6 H); 5.62 and 5.90 (tand dd, together 1 H); 6.10 and 6.25 (both d, together 1 H); 6.70 and6.89 (both m, together 1 H); 9.48 and 9.52 both br, together 1 H).

HPLC:

7.15 min (H8).

For biological testing, the title compound was transferred into itsacetate salt by lyophilization with 0.5M acetic acid (40 ml).

HPLC-method H8:

The RP-analysis was performed using UV detections at 214, 254, 276, and301 nm on a 218TP54 4.6 mm×150 mm C-18 silica column, which was elutedat 1 mL/min at 42° C. The column was equilibrated with 5% acetonitrile,85% water and 10% of a solution of 0.5% trifluoroacetic acid in waterand eluted by a linear gradient from 5% acetonitrile, 85% water and 10%of a solution of 0.5% trifluoroacetic acid to 90% acetonitrile and 10%of a solution of 0.5% trifluoroacetic acid over 15 min.

Example 18

(2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-N-(2-(2-(3-hydroxypropoxy)phenyl)ethyl)-N-methyl-3-(2-naphthyl)propionamide##STR173## 2-(2-Benzyloxyphenyl)-N-methylacetamide ##STR174##2-(2-Benzyloxyphenyl)acetic acid (15.0 g, 62 mmol) was dissolved indichloromethane (270 ml) and N,N-dimethylformamide (70 ml).1-Hydroxybenzotriazole (8.37 g, 62 mmol) was added. The solution wascooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimidehydrochloride (11.89 g, 62 mmol) was added. The reaction mixture wasstirred for 20 min. A 8.0M solution of methylamine in ethanol (38.8 ml,310 mmol) was added. The solution was stirred for 16 h, while it waswarming up to room temperature. It was diluted with ethyl acetate (500ml) and washed with a 10% aqueous solution of sodium hydrogen sulfatesolution (500 ml). The aqueous phase was extracted with ethyl acetate(2×300 ml). The combined organic layers were washed with a saturatedaqueous solution of sodium hydrogen carbonate (400 ml) and dried overmagnesium sulfate. The solvent was removed in vacuo. The remainingcrystals were washed with a mixture of ethyl acetate/heptane 1:4 (100ml). They were dried in vacuo. They were dissolved in ethyl acetate. Thesolution was washed with a saturated aqueous solution of sodium hydrogencarbonate (2×500 ml) and dried over magnesium sulfate. The solvent wasremoved in vacuo to give 10.24 g of2-(2-benzyloxyphenyl)-N-methylacetamide.

¹ H-NMR (DMSO-d₆): d 2.57 and 2.58 (both s, together 3 H); 3.44 (s, 2H); 5.60 and 5.61 (both s, together 2 H); 6.89 (t, 1 H); 7.03 (d, 1 H);7.19 (m, 2 H); 7.30 (m, 1 H); 7.38 (m, 2 H); 7.45 (m, 2 H); 7.69 (br, 1H).

N-(2-(2-Benzyloxyphenyl)ethyl)-N-methylamine ##STR175## At 0° C., asolution of 2-(2-benzyloxyphenyl)-N-methylacetamide (9.39 g, 36.8 mmol)in tetrahydroufran (150 ml) was added dropwise to a suspension of sodiumborohydride (1.67 g, 44.12 mmol) in tetrahydrofuran (100 ml). After theaddition was finished, a solution of iodine (4.67 g, 18.39 mmol) intetrahydrofuran (200 ml) was added dropwise. The solution was warmed toreflux for 16 h. It was cooled to 0° C. Methanol (200 ml) was addeddropwise. The solvent was removed in vacuo. The residue was dissolved inan aqueous 20% sodium hydroxide solution (200 ml) and tert-butyl methylether (200 ml). The phases were separated. The aqueous phase wasextracted with tert-butyl methyl ether (3×75 ml). The combined organiclayers were dried over magnesium sulfate. The solvent was removed invacuo. The crude product was purified by flash chromatography on silica(400 9), using dichloromethane/methanol/25% aqueous ammonia as eluent(100:10:1), to give 4.38 g ofN-(2-(2-benzyloxyphenyl)ethyl)-N-methylamine.

¹ H-NMR (CDCl₃): d 2.40 (s, 3 H); 2.70 (br, 1 H); 2.87 (m, 4 H); 5.07(s, 2 H); 6.89 (m, 2 H); 7.18 (m, 2 H); 7.35 (m, 5 H).

N-(2-(2-Benzyloxyphenyl)ethyl)-N-methylcarbamic acid tert-butyl ester##STR176## A solution of di-tert-butyl dicarbonate (3.80 g, 17.4 mmol)in tetrahydrofuran (8.7 ml) was added dropwise to a solution ofN-(2-(2-benzyloxyphenyl)ethyl)-N-methylamine (3.82 g, 15.8 mmol) intetrahydrofuran (8.7 ml) and an 1N aqueous sodium hydroxide solution(17.4 ml, 17.4 mmol). The reaction mixture was stirred for 16 h at roomtemperature. It was diluted with ethyl acetate (200 ml) and water (200ml). The phases were separated. The aqueous phase was extracted withethyl acetate (200 ml). The combined organic layers were washed with asaturated aqueous solution of sodium hydrogen carbonate (400 ml) anddried over magensium sulfate. The solvent was removed in vacuo. Thecrude product was purified by flash chromatography on silica (225 g),using ethyl acetate/heptane 1:4 as eluent, to give 4.73 g ofN-(2-(2-benzyloxyphenyl)ethyl)-N-methylcarbamic acid tert-butyl ester.

¹ H-NMR (CDCl₃): d 1.32 and 1.42 (both br, tohgether 9 H); 2.74 and 2.86(both br, together 5 H); 3.43 (t, 2 H); 5.08 (s, 2 H); 6.89 (m, 2 H);7.17 (br, 2 H); 7,40 (m, 5 H).

N-(2-(2-Hydroxyphenyl)ethyl)-N-methylcarbamic acid tert-butyl ester##STR177## N-(2-(2-Benzyloxyphenyl)ethyl)-N-methylcarbamic acidtert-butyl ester (4.66 g, 13.65 mmol) was dissolved in ethanol (35.6 ml)and was hydrogenated at room pressure in the presence of 10% palladiumon activated carbon for 16 h. The reaction mixture was filtered througha plug of celite. The celite was washed with ethyl acetate (50 ml). Theliquid phases were collected. The solvents were removed in vacuo. Thecrude product was purified by flash chromatography on silica (300 g),using ethyl acetate/heptane (1:2) as eluent, to give 2.84 g ofN-(2-(2-hydroxyphenyl)ethyl)-N-methylcarbamic acid tert-butyl ester.

¹ H-NMR (CDCl₃): d 1.45 (s, 9 H); 2.86 (t, 2 H); 2.90 (s, 3 H); 3.34(br, 2 H); 6.81 (t, 1 H); 6.87 (br, 1 H), 7.03 (d, 1 H), 7.12 (t, 1 H).

{2- 2-(3-Hydroxypropoxy)phenyl!ethyl}-N-methylcarbamic acid tert-butylester ##STR178## N-(2-(2-Hydroxyphenyl)ethyl)-N-methylcarbamic acidtert-butyl ester (702 mg, 2.79 mmol) was dissolved inN,N-dimethylformamide (6 ml). Potassium carbonate (1.93 g, 13.97 mmol)and cesium chloride (24 mg, 0.14 mmol) were added. 3-bromo-1-propanol(0.28 ml, 3.07 mmol) was added. The reaction mixture was stirred at 80°C. for 16 h. It was cooled to room temperature and diluted with ethylacetate (75 ml) and water (75 ml). The phases were separated. Theaqueous phase was extracted with ethyl acetate (2×50 ml). The combinedorganic layers were washed with a 10% aqueous solution of sodiumhydrogen sulfate solution (70 ml) and a saturated aqueous solution ofsodium hydrogen carbonate (70 ml). They were dried over magnesiumsulfate. The solvent was removed in vacuo. The crude product waspurified by flash chromatography on silica (80 g), using ethylacetate/heptane (1.1) as eluent, to give 606 mg of {2-2-(3-hydroxypropoxy)phenyl!ethyl}-N-methylcarbamic acid tert-butylester.

¹ H-NMR (CDCl₃): d 1.39 (br, 9 H); 2.06 (m, 2 H); 2.82 (br, 5 H); 3.45(br, 2 H); 3.90 (br, 2 H); 4.14 (t, 2 H); 6.85 (m, 2 H); 7.09 (br, 1 H);7.17 (t, 1 H).

3- 2-(2-Methylaminoethyl)phenoxy!propan-1-ol ##STR179## {2-2-(3-Hydroxypropoxy)phenyl!ethyl}-N-methylcarbamic acid tert-butyl ester(0.587 g, 1.90 mmol) was dissolved in dichloromethane (5 ml). Thesolution was cooled to 0° C. Trifluoroacetic acid (5 ml) was added. Thereaction mixture was stirred for 30 min at 0° C. Dichloromethane (50 ml)was added. A saturated aqueous solution of sodium hydrogen carbonate (50ml) was added dropwise. Solid sodium hydrogen carbonate was added, untilpH 7 was obtained. The phases were separated. The aqueous solution wasextracted with dichloromethane (3×70 ml). The aqueous phase was madebasic to pH 14 with a 20% aqueous sodium hydroxide solution. It wasextracted with tert-butyl methyl ether (3×100 ml). The tert-butyl methylether extracts were combined and dried over magnesium sulfate. Thesolvent was removed in vacuo to give 227 mg of crude 3-2-(2-methylaminoethyl)phenoxy!propan-1-ol. The crude product was use din the next step without further purification.

¹ H-NMR (CDCl₃): d 1.19 (s, 1 H); 2.03 (m, 2 H); 2,25 (br, 1 H); 2.39(s, 3 H); 2.83 (m, 4 H); 3.87 (m, 2 H); 4.10 (m, 2 H); 5.90 (m, 2 Hr;7.15 (m, 2 H).

N- (1R)-1-(N-{2-2-(3-Hydroxypropoxy)phenyl!ethyl}-N-methylcarbamoyl)-2-(2-naphthyl)ethyl!-N-methylcarbamicacid tert-butyl ester ##STR180##(2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid (357 mg, 1.08 mmol) and 1-hydroxy-7-azabenzotriazole (148 mg, 1.08mmol) were dissolved in N,N-dimethylformamide (2 ml) and dichloromethane(2 ml). The solution was cooled to 0° C.N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (208 mg,1.08 mmol) was added. The reaction mixture was stirred for 20 min at 0°C. A solution of 3- 2-(2-methylaminoethyl)phenoxy!propan-1-ol (227 mg,1.08 mmol) in dichloromethane (2 ml) and ethyldiisopropyoamine (0.2 ml,1.08 mmol) were added. The reaction mixture was stirred for 16 h, whileit was warming up to room temperature. It was diluted with ethyl acetate(100 ml) and washed with a 10% aqueous solution of sodium hydrogensulfate (100 ml). The aqueous phase was extracted with ethyl acetate(2×50 ml). The combined organic layeres were washed with a saturatedaqueous solution of sodium hydrogen carbonate (100 ml) and dried overmagnesium sulfate. The solvent was removed in vacuo. The crude productwas purified by flash chromatography on silica (30 g), using ethylacetate/heptane (2:1) as eluent, to give 383 mg of N- (1R)-1-(N-{2-2-(3-hydroxypropoxy)phenyl!ethyl}-N-methylcarbamoyl)-2-(2-naphthyl)ethyl!-N-methylcarbamicacid tert-butyl ester.

¹ H-NMR (CDCl₃, selected values): d 0.98, 1.05, 1.18, and 1.26 (all s,together 9 H); 4.28, 4.98, 5.18, and 5.32 (m, m, dd, and t, together 1H).

(2R)-N-(2-(2-(3-Hydroxypropoxy)phenyl)ethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide##STR181## A solution of N- (1R)-1-(N-{2-2-(3-hydroxypropoxy)phenyl!ethyl}-N-methylcarbamoyl)-2-(2-naphthyl)ethyl!-N-methylcarbamicacid tert-butyl ester (383 mg, 0.74 mmol) in dichloromethane (4 ml) wascooled to 0° C. Trifluoroacetic acid (4 ml) was added. The reactionmixture was stirred for 105 min at 0° C. Dichloromethane (40 ml) wasadded. A saturated aqueous solution of sodium hydrogen carbonate (40 ml)was added dropwise. Solid sodium hydrogen carbonate was added, until pH7 was obtained. The phases were separated. The aqueous phase wasextracted with dichloromethane (3×60 ml). The combined organic layerswere dried over magnesium sulfate. The solvent was removed in vacuo. Thecrude product was purified by flash chromatography on silica (30 g),using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent,to give 216 mg of(2R)-N-(2-(2-(3-hydroxypropoxy)phenyl)ethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide.

¹ H-NMR (CDCl₃, selected values): d 2.00 (m, 2 H); 2.12 and 2.19 (boths, together 3 H); 2.47 and 2.91 (both s, together 3 H).

((3E)-4-N-{ 1R)-1-(N-{2-2-(3-Hydroxypropoxy)phenyl!ethyl}-N-methylcarbamoyl)-2-(2-naphthyl)ethyl!-N-methylcarbamoyl}-1,1-dimethylbut-3-enyl)carbamicacid tert-butyl ester ##STR182##(2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid (125 mg,0.514 mmol) and 1-hydroxy-7-azabenzotriazole (70 mg, 0.514 mmol) weredissolved in dichloromethane (2 ml) and N,N-dimethylformamide (2 ml).The solution was cooled to 0° C.N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (99 mg,0.514 mmol) was added. The reaction mixture was stirred for 20 min at 0°C. A solution of(2R)-N-(2-(2-(3-hydroxypropoxy)phenyl)ethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide(216 mg, 0.514 mmol) in dichloromethane (2 ml) and ethyldiisopropylamine(0.09 ml, 0.514 mmol) were added. The reaction mixture was stirred for16 h, while it was warming up to room temperature. It was diluted withethyl acetate (70 ml) and washed with a 10% aqueous solution of sodiumhydrogen sulfate solution (70 ml). The aqueous phase was extracted withethyl acetate (2×40 ml). The combined organic layers were washed with asaturated aqueous solution of sodium hydrogen carbonate and dried overmagnesium sulfate. The solvent was removed in vacuo. The crude productwas purified by flash chromatography on silica (15 g), using ethylacetate/heptane (3:1) as eluent, to give 270 mg of ((3E)-4-N-{1R)-1-(N-{2-2-(3-hydroxypropoxy)phenyl!ethyl}-N-methylcarbamoyl)-2-(2-naphthyl)ethyl!-N-methylcarbamoyl}-1,1-dimethylbut-3-enyl)carbamicacid tert-butyl ester.

¹ H-NMR (CDCl₃, selected values): d 1.05, 1.11, 1.34, and 1.41 (all s,together 15 H); 2.82, 2.90, and 3.02 (all s, together 6 H); 5.46 and5.83 (dd and t, together 1 H); 5.95 and 6.20 (both d, together 1 H);6.45 (m, 1 H).

A solution of ((3E)-4-N-{ 1R)-1-(N-{2-2-(3-hydroxypropoxy)phenyl!ethyl}-N-methylcarbamoyl)-2-(2-naphthyl)ethyl!-N-methylcarbamoyl}-1,1-dimethylbut-3-enyl)carbamicacid tert-butyl ester (176 mg, 0.27 mmol) in dichloromethane (2 ml) wascooled to 0° C. Trifluoroacetic acid (2 ml) was added. The reactionmixture was stirred at 0° C. for 35 min. Dichloromethane (20 ml) wasadded. A saturated solution of sodium hydrogen carbonate (30 ml) wasadded dropwise. Solid sodium hydrogen carbonate was added, until pH 7was obtained. The phases were separated. The aqueous phase was extractedwith dichloromethane (3×30 ml). The combined organic layers were driedover magnesium sulfate. The solvent was removed in vacuo. The crudeproduct was purified by flash chromatography on silica, usingdichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent togive 64 mg of the title compound.

¹ H-NMR (CDCl₃, selected values): d 0.98, 0.99, 1.10, and 1.11 (all s,together 6 H); 2.82, 2.85, 2.91, and 3.03 (all s, together 6 H); 5.47and 5.84 (both dd, together 1 H); 5.95 and 6.19 (both d, together 1 H);6.55 (m, 1 H).

HPLC:

32.57 min (A1).

34.60 min (B1).

MS: 546.0 ( M+H!⁺).

For biological testing, the title compound was transferred into itsacetate salt by lyophilization with 0.5M actic acid (40 ml).

Example 19

1-((2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl-2-benzyl-4-ethylsemi-carbazide ##STR183##N'-Benzylidenehydrazinecarboxylic acid tert-butyl ester: ##STR184## To asolution of t-butyl carbazate (2.0 g, 15.1 mmol) in 99% ethanol (20 ml)was added benzaldehyde (1.6 g, 15.1 mmol) and the mixture was stirredfor 30 min. Then the mixture was cooled to 0° C. and the precipitate wasseparated and washed with cold ethanol and dried in vacuo to give 2.7 g(81%) of N'-benzylidenehydrazinecarboxylic acid tert-butyl ester.

¹ H-NMR (CDCl₃): d 1.5 (s, 9H) 7.35 (m, 3H) 7.65 (m, 2H) 7.85 (s, 1H)8.0 (s, 1 H)

N'-Benzylhydrazinecarboxylic acid tert-butyl ester: ##STR185## To asolution of N'-benzylidenehydrazinecarboxylic acid tert-butyl ester (2.7g, 12.3 mmol) in tetrahydrofuran (100 ml) was added 10% palladium oncarbon (0.3 g) and the mixture was hydrogenated with 280 ml of hydrogenfor 40 min at atmospheric pressure. The mixture was filtered through aplug of celite and the filtrate was concentrated in vacuo to give 2.63 gof N'-benzylhydrazinecarboxylic acid tert-butyl ester.

¹ H-NMR (CDCl₃): d 1.5 (s, 9H) 4.0 (s, 2H) 4.2 (b, 1H) 6.1 (b, 1H)7.2-7.4 (m, 5H).

2-Benzyl-1-tert-butoxycarbonyl-4-ethylsemicarbazide: ##STR186## To asolution of N'-benzylhydrazinecarboxylic acid tert-butyl ester (2.5 g,11.8 mmol) in 99% ethanol (40 ml) was added ethyl isocyanate (1.1 g,15.2 mmol) and the mixture was stirred for 2 h. Then the mixture wasconcentrated in vacuo and chromatographed on silica (20 g) with petrolether/ethyl acetate 3:2 to give 3.0 g of2-benzyl-1-tert-butoxycarbonyl-4-ethylsemicarbazide.

¹ H-NMR (CDCl₃): d 1.1 (t, 3H) 1.45 (s, 9H) 3.3 (m, 2H) 3.9-5.0 (b, 2H)5.35 (t, 1H) 5.9 (s, 1H) 7.2-7.4 (m, 5H).

¹³ C-NMR (CDCl₃): 15.0 (--CH₂ CH₃), 27.6 (--C(CH₃)₃) 34.9 (--CH₂ CH₃)50.0 (--C(CH₃)₃) 81.7 (--CH₂ --C₆ H₅) 127.3-128.6 (--C₂ --CH₆ H₅) 135.9(--CH₂ --C₆ H₅) 154.0 (--OCON) 157.1 (--NCON).

2-Benzyl-4-ethylsemicarbazide: ##STR187## A solution of of2-benzyl-1-tert-butoxycarbonyl-4-ethylsemicarbazide (2.8 g, 9.6 mmol) in50% trifluoroacetic acid in dichloromethane (10 ml) was stirred for 10min at room temperature. Then saturated sodium bicarbonate was addeduntil pH >7 and the aqueous layer was extracted with dichloromethane(2×10 ml) and the combined organic layers were dried (magnesium sulfate)and concentrated in vacuo. The obtained oil was chromatographed onsilica (100 g) with ethyl acetate as eluent to give 1.7 g of2-benzyl-4-ethylsemicarbazide.

¹ H-NMR (CDCl₃): d 1.15 (t, 3H) 3.3 (m, 2H)4.7 (s, 2H) 7.2-7.4 (m, 5H).

2-Benzyl-1-(2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionyl!-4-ethylsemicarbazide:##STR188## To a solution of(2R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-(2-naphthyl)propionicacid (2.6 g, 7.9 mmol) in dichloromethane (20 ml) was added1-hydroxy-7-azabenzotriazole (1.1 g, 8.0 mmol) and1-ethyl-3-dimethylaminopropyl carbodiimide hydrochloride (1.6 g, 8.6mmol) and the mixture was stirred at 30 min at room temperature. Then2-benzyl-4-ethylsemicarbazide (1.3 g, 6.6 mmol) anddiisopropylethylamine (1.5 ml, 8.6 mmol) in dichloromethane (20 ml) wereadded and the mixture was stirred overnight. The mixture was washed withsaturated sodium bicarbonate (2×50 ml), dried (magnesium sulfate) andconcentrated in vacuo. The obtained product was chromatographed onsilica (100 g) with petrol ether/ethyl acetate 1:1 to give 3.0 g (90%)of 2-benzyl-1-(2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-(2-naphtyl)propionyl!-4-ethylsemicarbazide.

¹ H-NMR (CDCl₃): d 0.9 (t, 3H) 1.45 (s, 9H) 2.65 (s, 3H) 3.1 (m, 2H) 3.2(m, 1H) 3.3 (dd, 2H) 4.4 (b, 2H) 4.9 (b, 1H) 5.2 (b, 1H) 6.9-7.8 (m,12H).

2-Benzyl-1-(2R)-2-N-methylamino-3-(2-naphthyl)propionyl!-4-ethylsemicarbazide:##STR189## To a solution of of 2-benzyl-1-(2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionyl!-4-ethylsemicarbazide(2.9 g, 5.7 mmol) in dichloromethane (15 ml) at 0° C. was addedtrifluoroacetic acid (5 ml) and the mixture was allowed to stir for 3 hat 0° C. Then sodium bicarbonate was added until pH >7 and the aqueouslayer was extracted with dichloromethane (3×25 ml) and the combinedorganic layers were dried (magnesium sulfate) and concentrated to 2.0 gof 2-benzyl-1-(2R)-2-N-methylamino-3-(2-naphthyl)propionyl!-4-ethylsemicarbazide.

¹ H-NMR (CDCl₃): d 0.9 (t, 3H) 2.1 (s, 3H) 3.0 (m, 2H) 3.3 (dd, 2H) 4.6(t, 1H) 4.7 (dd, 2H) 7.1-7.8 (m, 12H) 8.3 (s, 1H).

2-Benzyl-1-((2R)-2-(N-((2E)-5-(N-tert-butoxycarbonyl)amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-4-ethylsemicarbazide:##STR190## To a solution of(2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid (0.5 g, 2.1mmol) in dichloromethane (20 ml) were added 1-hydroxy-7-azabenzotriazole(336 mg, 2.5 mmol) and 1-ethyl-3-dimethylaminopropylcarbodiimidehydrochloride (5.5 g, 2.9 mmol) and the mixture was stirred at 30 min atroom temperature. Then 2-benzyl-1-(2R)-2-N-methylamino-3-(2-naphthyl)propionyl!-4-ethylsemicarbazide (0.5g, 1.2 mmol) and diisopropylethylamine (0.4 ml, 2.3 mmol) indichloromethane (20 ml) were added and the mixture was stirredovernight. The mixture was washed with saturated sodium bicarbonate(2×20 ml), dried (magnesium sulfate) and concentrated in vacuo. Theobtained product was chromatographed on silica (20 g) with petrolether/ethyl acetate 1:1 to give 0.68 g of2-benzyl-1-((2R)-2-(N-((2E)-5-(N-tert-butoxycarbonyl)amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-4-ethylsemicarbazide.

¹ H-NMR (CDCl₃): d 0.9 (t, 3H) 1.25 (s, 6H) 1.4 (s, 9H) 2.65 (d, 2H) 2.9(s, 3H) 3.0 (m, 2H) 3.1 (m, 1H) 3.5 (m, 1H) 4.4 (s, 1H) 4.7 (b, 1H) 5.4(b, 1H) 5.1 (b, 1H) 6.1 (d, 1H) 6.8 (m, 1H) 6.9-7.8 (m, 12H).

To a solution of2-benzyl-1-((2R)-2-(N-((2E)-5-(N-tert-butoxycarbonyl)amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-4-ethylsemicarbazide(0.66 g, 1.0 mmol) in dichloromethane (5 ml) was added trifluoroaceticacid (2.5 ml) at 0° C. and stirred for 2 h. Then sodium bicarbonate wasadded until pH >7 and the aqueous layer was extracted withdichloromethane (2×10 ml) and the combined organic layers were dried(magnesium sulfate) and concentrated in vacuo. The obtained product wasdissolved in water (20 ml) and 1N acetic acid (2 ml) and the mixture waslyophilized to 0.5 g of the acetate salt of the title compound.

HPLC

(A1): R_(t) =31.3 min

(B1): R_(t) =33.0 min

LC-MS: 530.2 (M+H)⁺

¹ H-NMR (DMSO) (selected peaks): d 0.9 (t, 3H) 1.1 (s, 6H) 2.7 (s, 3H)6.25 (d, 1H) 6.6 (m, 1H) 7.2-7.9 (m, 12H).

Example 20

1-((2S)-2-(N-(2-(((2R)-pyrrolidin-2-yl)methoxy)acetyl)-N-methylamino)-3-(2-naphthyl)propionyl-2-benzyl-4-ethylsemicarbazide ##STR191##(2S)-2-(((Carboxy)methoxy)methyl)pyrrolidin-1-carboxylic acidtert-butylester: ##STR192## To a solution ofN-t-butyloxycarbonyl-(S)-prolinol (5.0 g, 25 mmol) in 1,2-dichloroethane(500 ml) rhodium(II)acetate (180 mg) was added and the mixture washeated to 80° C. Ethyldiazoacetate (3.9 ml, 37 mmol) in1,2-dichloroethane (180 ml) was added over a period of 90 min and themixture was heated at 80° C. for 3 hours. Then another portion of ethyldiazoacetate (1.3 ml, 12 mmol) in 1,2-dichloroethane (40 ml) was addedand the mixture was refluxed for 6 hours. The mixture was cooled to roomtemperature and washed with saturated sodium bicarbonate (2×100 ml) andbrine (100 ml), dried (magnesium sulfate) and concentrated in vacuo. Thecrude product was chromatographed on silica (300 g) with petrolether/ethyl acetate 4:1 as eluent to give 4.7 g of(2S)-2-(((ethoxycarbonyl)methoxy)methyl)pyrrolidin-1-carboxylic acidtert-butylester. The obtained product was dissolved in 1M lithiumhydroxide in water/methanol 1:3 (50 ml) and stirred at room temperatureovernight. The mixture was concentrated in vacuo, water (20 mL) wasadded and washed with ether (20 mL). The aqueous phase was acidified topH 4 with 1M aqueous hydrogen chloride, extracted with ethyl acetate(2×100 ml) and the combined organic layers were dried (magnesiumsulfate) and concentrated in vacuo to give 3.6 g of(2S)-2-(((carboxy)methoxy)methyl)-pyrrolidin-1-carboxylic acidtert-butyl ester.

1H-NMR (CDCl₃): d 1.45 (2, 9H) 1.90 (m, 4H) 3.55 (t, 2H) 3.60 (m, 3H)4.10 (s, 2H) 10.6 (s, 1H).

To a solution of(2S)-2-(((carboxy)methoxy)methyl)-pyrrolidin-1-carboxylic acidtert-butylester (0.97 g, 3.7 mmol) in dichloromethane (15 ml) were added1-hydroxy-7-azabenzotriazole (0.51 g, 3.7 mmol) and1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride (0.79 g, 4.1mmol) and the mixture was stirred at 30 min at room temperature. Then2-benzyl-1-(2R)-2-methylamino-3-(2-naphthyl)propionyl!-4-ethylsemicarbazide (0.75g, 1.9 mmol) and diisopropylethylamine (0.42 ml, 2.4 mmol) indichloromethane (15 ml) were added and the mixture was stirredovernight. The mixture was washed with saturated sodium bicarbonate(2×20 ml), dried (magnesium sulfate) and concentrated in vacuo. Theobtained product was chromatographed on silica (20 g) with petrolether/ethyl acetate 1:1. The chromatographed product was dissolved indichloromethane (10 ml) and trifluoroacetic acid (2.5 ml) was added at0° C. and stirred for 2 h. Then sodium bicarbonate was added until pH >7and the aqueous layer was extracted with dichloromethane (2×10 ml) andthe combined organic layers were dried (magnesium sulfate) andconcentrated in vacuo. The obtained product was dissolved in water (20ml) and 1N acetic acid (2 ml) and the mixture was lyophilized to 0.88 gof the acetate salt of the title compound.

HPLC

(A1): R_(t) =31.1

(B1): R_(t) =32.6

LC-MS: 546.0 (M+H)⁺

Example 21

1-((2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-3-(2-naphthyl)propionyl)-2-benzyl-4-ethylsemicarbazide##STR193## (2-t-Butoxycarbonylamino-2-methylpropoxy)acetic acid:##STR194## A solution of 2-t-butoxycarbonylamino-2-methylpropanol (5.0g, 26.46 mmol) and rhodium(II)acetate (90 mg) in dichloroethane (500 ml)was heated to 80° C. Then ethyl diazoacetate (4.0 g, 34.78 mmol) wasadded over a period of 1 h and the mixture was stirred at reflux for 3h. Another portion of rhodium(II)acetate (90 mg) was added and themixture was refluxed for another 5 h. The mixture was cooled overnightand saturated sodium bicarbonate (500 ml) was added, the layers wereseparated and the organic layer was washed twice with saturated sodiumbicarbonate (2×200 ml) and dried (magnesium sulfate) and concentrated invacuo. The obtained product was dissolved in 1M lithium hydroxide inmethanol/water 3:1 (200 ml) and stirred overnight. The solvent wasremoved in vacuo to a minimum, water (50 ml) was added (pH >9) and themixture was washed with ether (100 ml). Then 1M hydrochloric acid wasadded until pH <4 and the mixture was extracted with ethyl acetate (100ml) and the combined organic layers were dried (magnesium sulfate) andconcentrated in vacuo to give 2.5 g of(2-t-butoxycarbonylamino-2-methylpropoxy) acetic acid.

H1-NMR (CDCl₃): d 1.3 (s, 6H) 1.45 (s, 9H) 3.5 (s, 2H) 4.15 (s, 2H) 9.9(b, 1H).

To a solution of (2-t-butoxycarbonylamino-2-methylpropoxy) acetic acid(0.93 g, 3.7 mmol) in dichloromethane (15 ml) were added1-hydroxy-7-azabenzotriazole (0.51 g, 3.7 mmol) and1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride (0.79 g, 4.1mmol) and the mixture was stirred at 30 min at room temperature. Then2-benzyl-1-(2R)-2-N-methylamino-3-(2-naphthyl)propionyl!-4-ethylsemicarbazide (0.75g, 1.9 mmol) and diisopropylethylamine (0.42 ml, 2.4 mmol) indichloromethane (15 ml) were added and the mixture was stirredovernight. The mixture was washed with saturated sodium bicarbonate(2×20 ml), dried (magnesium sulfate) and concentrated in vacuo. Theobtained product was chromatographed on silica (20 g) with petrolether/ethyl acetate 1:1. The chromatographed product was dissolved indichloromethane (10 ml) and trifluoroacetic acid (2.5 ml) was added at0° C. and stirred for 2 h. Then sodium bicarbonate was added until pH >7and the aqueous layer was extracted with dichloromethane (2×10 ml)andthe combined organic layers were dried (magnesium sulfate) andconcentrated in vacuo. The obtained product was dissolved in water (20ml) and 1N acetic acid (2 ml) and the mixture was lyophilized to 0.98 gof the acetate salt of the title compound.

HPLC

(A1): R_(t) =31.0

(B1): R_(t) =32.6

LC-MS: 534.2 (M+H)⁺

Example 22

(3R)-4-((2E)-5-Amino-5-methylhex-2-enoyl)-3-((2-naphthyl)methyl)-1-phenethylpiperazin-2-one##STR195##(2R)-2-((2-(tert-Butoxycarbonylamino)ethyl)amino)-3-(2-naphthyl)propionicacid methylester. ##STR196## (2R)-2-Amino-3-(2-naphthyl)propionic acid(5, 0 g, 23 mmol) was added to methanol (150 ml) and thionylchloride(2.0 ml; 23 mmol) was added dropwise and the mixture was stirredovernight and then refluxed for 2.5 h. The solvent was removed in vacuoand the residue was dissolved in a mixture of methanol (95 ml) andacetic acid (5 ml). (2-Oxoethyl)carbamic acid tert-butyl ester (3.4 g,23 mmol, prepared as in Dueholm et al. Org. Prep. Proced. Int. (1993),457), sodium cyanoborohydride (1.9 g, 31 mmol) and molecular sieves (50g, Fluka, 3Å) were added and the mixture was left overnight. The mixturewas filtered and the filtrate was added to water (200 ml) and extractedwith methylene chloride (3×100 ml). The combined organic phases weredried (magnesium sulphate), and the solvent was removed in vacuo. Theresidue was chromatographed on silica (3×30 cm) to afford 3.55 g of(2R)-2-((2-(tert-butoxycarbonylamino)ethyl)amino)-3-(2-naphthyl)propionicacid methylester.

¹ H-NMR: (CDCl₃): d 1.39 (s, 9H); 2.56 (m, 1H); 2.75 (m, 1H); 3.09 (m,3H); 3.59 (m, 1H); 3.65 (s, 3H); 7.28-7.81 (7 arom. H)

(3R)-3-((2-Naphthyl)methyl)piperazin-2-one. ##STR197##(2R)-2-((2-(tert-butoxycarbonylamino)ethyl)amino)-3-(2-naphthyl)propionicacid methylester (3.4 g, 9.1 mmol) was stirred for 1 h in a mixture ofTFA (5 ml) and methylene chloride(5 ml). The volatiles were removed invacuo and the residue was dissolved in a mixture of water (40 ml) andmethanol (100 ml). Sodium hydrogencarbonate (2.3 g) was added and themixture was stirred overnight. The solvent was removed in vacuo and theresidue was dissolved in water (40 ml) and extracted with ethyl acetate(10×50 ml). The combined organic phases were dried (magnesium sulphate)and the solvent was removed in vacuo to afford 1.96 g of(3R)-3-((2-naphthyl)methyl)piperazin-2-one.

¹ H-NMR: (CDCl₃ ; selected peaks for major rotamer): d 2.95 (m, 1H);3.05 (m, 2H); 3.24 (m, 1H); 3.39 (m, 1H); 3.59 (dd, 1H); 3.72 (dd, 1H)

(2R)-2-(2-Naphthyl)methyl-3-oxo-4-phenethylpiperazine-1-carboxylic acidtert-butyl ester ##STR198## (3R)-3-((2-Naphthyl)methyl)piperazin-2-one(1.9 g; 7.9 mmol) and di-tert-butyl dicarbonate (2.1 g; 9.5 mmol) wassuspended in a mixture of THF (20 ml) and aqueous sodium hydroxide (1M,8 ml) and stirred overnight. The solvent was removed in vacuo and water(30 ml) was added. The aqueous phase was extracted with ethyl acetate(2×50 ml). The combined organic phases were dried (magnesium sulphate)and the solvent was removed in vacuo. The residue was dissolved in amixture of DMSO (15 ml) and potassium hydroxide (1.3 g).(2-bromoethyl)benzene (2.2 g, 11 mmol) was added and the mixture wasstirred for 1 h. Water (30 ml) and methylene chloride (60 ml) wereadded. The organic phase was washed with water (5×10 ml) and the solventwas removed in vacuo. The residue was chromatographed on silica (3×40cm) using ethyl acetate/heptane (1:2) as eluent to afford 1.25 g of(2R)-2-(2-naphthyl)methyl-3-oxo-4-phenethylpiperazine-1-carboxylic acidtert-butyl ester.

¹ H-NMR: (CDCl₃ ; selected peaks for major rotamer): d 1.15 (s, 9H);2.76 (t, 2H); 3.39 (t, 3H);

(2R)-2-(2-naphthyl)methyl-3-oxo-4-phenethylpiperazine-1-carboxylic acidtert-butyl ester (1.2 g; 2.7 mmol) was dissolved in a mixture of TFA (5ml) and methylene chloride (5 ml) and stirred for 15 min. Methylenechloride (30 ml) and aqueous sodium hydrogencarbonate (saturated) wasadded to pH 8. The mixture was extracted with methylene chloride (3×10ml) and the combined aqueous phases were dried (magnesium sulphate) andthe solvent was removed in vacuo. Part of the residue (400 mg 1.2 mmol)were added to a mixture of(2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid (282 mg; 1.2mmol); HOAt (158 mg; 1.2 mmol), EDAC (245 mg; 1.3 mmol) and DIEA (150mg; 1.2 mmol) and stirred overnight. Methylene chloride (50 ml) wasadded and the mixture was washed with aqueous sodium hydrogensulphate(10%; 50 ml); aqueous sodium hydrogencarbonate (saturated; 50 ml) andwater (50 ml). The organic phase was dried (magnesium sulphate) and thesolvent removed in vacuo. The residue was chromatographed on silica(2×20 cm) and the residue was dissolved in a mixture of TFA (2 ml) andmethylene chloride (2 ml) and stirred for 5 min. Methylene chloride andan aqueous solution of sodium hydrogenarbonate (sat.) was added to pH 8.The mixture was extracted with methylene chloride (2×10 ml). The organicphase was dried (magnesium sulphate) and the solvent was removed invacuo to afford 310 mg of the title compound.

¹ H-NMR: (CDCl₃ ; selected peaks for major rotamer): d 0.99 (s, 6H);4.51 (dd, 1H); 5.61 (d, 1H); 6.56 (m, 1H)

HPLC: (method A1): R_(t) =32.47 min.

PDMS: m/z 470.5 (M+H)⁺.

We claim:
 1. A compound of formula I ##STR199## wherein A is A¹ or A² ;Gis G¹ or G² ; D is ##STR200## wherein R⁵, R⁶, R⁷, R⁸, and R⁹independently are hydrogen, halogen, aryl, C₁₋₆ -alkyl or C₁₋₆ -alkoxy;E is hydrogen, --O--(CH₂)_(I) --R^(10a), ##STR201## wherein R¹⁰, R¹¹,R¹², R¹³ and R¹⁴ independently are hydrogen, halogen, aryl, C₁₋₆ -alkyl,C₁₋₆ -alkoxy, --CONR¹⁵ R¹⁶, --(CH₂)_(v) --NR¹⁵ SO₂ R¹⁷, --(CH₂)_(v)--NR¹⁵ COR¹⁶, --(CH₂)_(v) --OR¹⁷, --(CH₂)_(v) --OCOR¹⁶, --(CH(R¹⁵)R¹⁶,--(CH₂)_(v) --NR¹⁵ --CS--NR¹⁶ R¹⁸, --(CH₂)_(v) --NR¹⁵ --CO--NR¹⁶ R¹⁸,R¹⁵ and R¹⁶ independently are hydrogen or C₁₋₆ -alkyl optionallysubstituted with halogen, --N(R²⁶)R²⁷, hydroxyl, C₁₋₆ -alkoxy, C₁₋₆-alkoxycarbonyl, C₁₋₆ -alkyl-carbonyloxy or aryl, or R¹⁶ is ##STR202##wherein Q¹ is --CH<, T¹ and J¹ are independently --CH₂ --, --CO--, or avalence bond, t and u are independently 0, 1, 2, 3 or 4; R¹⁷ is C₁₋₆alkyl or phenyl optionally substituted with hydroxyl or aryl; R¹⁸ isC₁₋₆ alkyl; R²⁶ and R²⁷ are independently hydrogen or C₁₋₆ -alkyl; v is0, 1, 2 or 3; R^(10a) is hydrogen, aryl optionally substituted withhalogen or C₁₋₆ -alkyl, or C₁₋₆ -alkyl optionally substituted withhalogen or C₁₋₆ -alkyl, I is 0, 1, 2, or 3; A¹ is ##STR203## whereinR²⁹, R³³, R³⁴, R³⁵ and R³⁶ are independently hydrogen or C₁₋₆ alkyloptionally substituted with halogen, amino, hydroxyl or aryl; R³⁴ andR³⁵ may optionally form --(CH₂)_(i) --Z--(CH₂)_(j) --, wherein i and jindependently are 1 or 2 and Z is a valence bond; n, m and q areindependently 0, 1, 2, or 3; o and p are independently 0 or 1; M is--CR³⁷ ═CR³⁸ --, --O--, --S--, or a valence bond; R³⁷ and R³⁸ areindependently hydrogen, or C₁₋₆ -alkyl optionally substituted with aryl;A² is ##STR204## wherein R²⁹, R³³, R³⁴, R³⁵ and R³⁶ are independentlyhydrogen or C₁₋₆ -alkyl optionally substituted with halogen, amino,hydroxyl or aryl; R³⁴ and R³⁵ may optionally form --(CH₂)_(i)--Z--(CH₂)_(j) --, wherein i and j independently are 1 or 2 and Z is avalence bond; n, m and q are independently 0, 1, 2, or 3; o and p areindependently 0 or 1; M is --CR³⁷ ═CR³⁸ --, --O--, or --S--; R³⁷ and R³⁸are independently hydrogen, or C₁₋₆ -alkyl optionally substituted witharyl; G¹ is hydrogen, halogen, aryl, C₁₋₆ --alkyl, C₁₋₆ --alkoxy,--CONR³⁹ R⁴⁰, --(CH₂)_(e) --NR³⁹ SO₂ R⁴¹, --(CH₂)_(e) --NR³⁹ COR⁴⁰,--(CH₂)_(e) --OR⁴¹, --(CH₂)_(e) --OCOR⁴⁰, --CH(R³⁹)R⁴⁰, --CON³⁹ --NR⁴⁰R⁴², --(CH₂)_(e) --NR³⁹ --CS--NR⁴⁰ R⁴², --(CH₂)_(e) --NR³⁹ --CO--NR⁴⁰R⁴², R³⁹ and R⁴⁰ independently are hydrogen or C₁₋₆ -alkyl optionallysubstituted with halogen, --N(R⁵⁰)R⁵¹, hydroxyl, C₁₋₆ -alkoxy, C₁₋₆-alkoxycarbonyl, C₁₋₆ -alkylcarbonyloxy or aryl, or R⁴⁰ is ##STR205##wherein Q² is --CH<, J² and T² are independently --CH₂ --, --CO--, or avalence bond, x and y are independently 0, 1, 2, 3 or 4; R⁴¹ is C₁₋₆alkyl substituted with aryl; R⁴² is C₁₋₆ alkyl; R⁵⁰ and R⁵¹ areindependently hydrogen or C₁₋₆ -alkyl; e and f are independently 0, 1, 2or 3; G² is hydrogen or C₁₋₆ -alkyl; R¹ is hydrogen, or C₁₋₆ -alkyl; R²is hydrogen, --C(═O)--R⁵⁴ or C₁₋₆ -alkyl; R⁵⁴ is hydrgen or C₁₋₆ -alkyl,R³ and R⁴ are taken together to form ═S or ═O; L¹ is CR⁵⁷ ; L² is CR⁵⁸or N; R⁵⁷ and R⁵⁸ independently are hydrogen, C₁₋₆ -alkyl, optionallysubstituted with hydroxyl, halogen, C₁₋₆ -alkoxy, or aryl; a and bindependently are 0, 1, 2, or 3; with the proviso that:when G is G² andL¹ is CR⁵⁷ and L² is CR⁵⁸, then A is A² ; when G is G¹ and L¹ is CR⁵⁷and L² is CR⁵⁸, then A is A¹ and R² is --C(═O)--R⁵⁴ when L² is N, then Gis G¹ and A is A¹ ; or a pharmaceutically acceptable salt thereof. 2.The compound according to claim 1, wherein A is R³³ --NH--(CR³⁴R³⁵)_(p)(CH₂)_(m) --M--(CHR³⁶)_(o) --(CH₂)_(n) --wherein R³³ is hydrogenor C₁₋₆ alkyl optionally substituted with hydroxyl, R³⁴ and R³⁵ areindependently of each other C₁₋₆ alkyl, R³⁶ is hydrogen, M is --CR³⁷═CR³⁸ --or --O--, wherein R³⁷ and R³⁸ are hydrogen or C₁₋₆ alkyl, p is1, m is 1, o is 0 or 1 and n is 0 or
 1. 3. The compound according toclaim 1, wherein A is ##STR206## wherein R³³ is hydrogen or C₁₋₆ alkyl,R³⁴ and R³⁵ independently of each other are hydrogen or C₁₋₆ alkyl,m is0 or 1, n is 0 or 1, and p is 0 or
 1. 4. The compound according to claim1, wherein D is ##STR207## wherein R⁵, R⁶, R⁷, R⁸ and R⁹ independentlyof each other are hydrogen or aryl.
 5. The compound according to claim1, wherein D is ##STR208## wherein R⁵ and R⁶ independently of each otherare hydrogen or C₁₋₆ alkyl.
 6. The compound according to claim 1,wherein E is ##STR209## wherein R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ independentlyof each other are hydrogen, --(CH₂)_(v) --NR¹⁵ SO₂ R¹⁷, --(CH₂)_(v)--NR¹⁵ COR¹⁶ or --(CH₂)_(v) --OR¹⁷, wherein v is 0 or 1, R¹⁵ is hydrogenor C₁₋₆ alkyl, R¹⁶ is hydrogen or C₁₋₆ alkyl optionally substituted with--N(R²⁶)R²⁷, wherein R²⁶ and R²⁷ independently of each other arehydrogen or C₁₋₆ alkyl, R¹⁷ is C₁₋₆ alkyl or phenyl optionallysubstituted with hydroxyl or phenyl.
 7. The compound according to claim1, wherein G is hydrogen or --CONR³⁹ R⁴⁰, wherein R³⁹ and R⁴⁰independently of each other are hydrogen or C₁₋₆ alkyl.
 8. The compoundaccording to claim 1, wherein R² is hydrogen, --C(═O)--R⁵⁴ or C₁₋₆alkyl, wherein R⁵⁴ is C₁₋₆ alkyl.
 9. The compound according to claim 1,wherein R³ and R⁴ are taken together to form ═O.
 10. The compoundaccording to claim 1, wherein a is
 1. 11. The compound according toclaim 1, wherein b is 0 or
 1. 12. The compound according to claim 1,wherein L¹ is --CH--.
 13. The compound according to claim 1, wherein L¹is --CH-- or >N--.
 14. The compound according to claim 1, selected fromthe group consistingof1-((2R)-2-(N-((2E)-5-amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-2-benzyl-4-ethylsemicarbazide,1-((2R)-2-(N-((2-amino-2-methylpropoxy)acetyl)-N-methylamino)-3-(2-naphthyl)propionyl)-2-benzyl-4-ethylsemicarbazide,(2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionicacid N-methyl-N-phenethylamide, or the trifluoroacetate salt thereof,(2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionicacid N-methyl-N-(2-(2-(methylsulfonylamino)phenyl)ethyl)amide,(2R)-2-(N-((2E)-5-((2R)-2-hydroxypropylamino)-5-methylhex-2-enoyl)-N-methylamino)-N-methyl-3-(2-naphthyl)-N-phenethylpropionamide,or the trifluoroacetate salt thereof, (2E)-5-Amino-5-methylhex-2-enoicacidN-((1R)-2-(N-acetyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)amino)-1-((2-naphthyl)methyl)ethyl)amide,(2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-(N-methyl-N-(3-phenylpropyl)carbamoyl)-2-(2-naphthyl)ethyl)amide,(2E)-5-Methyl-N-methyl-5-(methylamino)-N-((1R)-1-(N-methyl-N-phenethylcarbamoyl)-2-(2-naphthyl)ethyl)hex-2-enamide,(2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methyl-3-(2-naphthyl)propionamide,(2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-N-methyl-3-(2-naphthyl)-N-(2-(2-methylsulfonylaminophenyl)ethyl)propionamide,(2E)-N-((1R)-1-(N-(2-(2-(2-Hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methyl-5-methyl-5-(methylamino)hex-2-enamide,3-Aminomethyl-N- (1R)-1-(N-{2-2-(2-hydroxyethoxy)phenyl!ethyl}-N-methylcarbamoyl)-2-(2-naphthyl)ethyl!benzamide,(2E)-5-Amino-5-methylhex-2-enoic acidN-((1R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methylcarbomoyl)-2-(2-naphthyl)ethyl)-N-methylamide,(2E)-5-Amino-5-methylhex-2-enoic acid N-((1R)-1-{N-2-(2-(benzenesulfonylamino)phenyl)ethyl!-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide,2-Amino-N-(2-(2-(N-((2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)ethyl)phenyl)acetamide,(2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-N-(2-(2-(3-hydroxypropoxy)phenyl)ethyl)-N-methyl-3-(2-naphthyl)propionamide,3-Aminomethyl-N- (1R)-1-(N-{2-2-(2-hydroxyethoxy)phenyl!ethyl}-N-methylcarbamoyl)-2-(2-naphthyl)ethyl!benzamide,and (2E)-5-Amino-5-methylhex-2-enoic acidN-((1R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methylcarbomoyl)-2-(2-naphthyl)ethyl)amide;or a pharmaceutically acceptable salt thereof.
 15. A pharmaceuticalcomposition comprising, as an active ingredient, a compound according toclaim 1 or a pharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier or diluent.
 16. A method ofstimulating the release of growth hormone from the pituitary, the methodcomprising administering to a subject in need thereof an effectiveamount of a compound according to claim 1 or a pharmaceuticallyacceptable salt thereof.